Onset Of Amyotrophic Lateral Sclerosis Symptoms Research Articles

Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice.

The pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression. Here, we tested if REL-1017 improves the disease phenotypes in the G93A SOD1 mouse, a well-established model of familial ALS, by examining survival and motor functions, as well as the expression of genes and proteins involved in neuroplasticity. We found a sex-dependent effect of REL-1017 in G93A SOD1 mice. A delay of ALS symptom onset, assessed as 10%-decrease of body weight (p < 0.01 vs. control untreated mice) and an extension of lifespan (p < 0.001 vs. control untreated mice) was observed in male G93A SOD1 mice. Female G93A SOD1 mice treated with REL-1017 showed an improvement of muscle strength (p < 0.01 vs. control untreated mice). Both males and females treated with REL-1017 showed a decrease in hind limb clasping. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles. In conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS.

Desloratadine alleviates ALS-like pathology in hSOD1G93A mice via targeting 5HTR2A on activated spinal astrocytes.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1G93A (hSOD1G93A) ALS model mice, and elucidated the underlying mechanisms. HSOD1G93A mice were administered DLT (20 mg·kg-1·d-1, i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1G93A mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1G93A mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice.

Time from amyotrophic lateral sclerosis symptom onset to key disease milestones: analysis of data from a multinational cross-sectional survey

Objective To determine the average time from Amyotrophic Lateral Sclerosis (ALS) symptom onset to 11 pre-defined milestones, overall and according to ALS progression rate and geographic location. Methods Data were drawn from the Adelphi Real World ALS Disease-Specific ProgrammeTM, a point-in-time survey of neurologists caring for people living with ALS (pALS) conducted in France, Germany, Italy, Spain, the United Kingdom and the United States from 2020–2021. ALS progression rate was calculated using time since symptom onset and ALS Functional Rating Scale Revised score. Results Survey results were available for N = 1003 pALS (progression rate for N = 867). Mean time from symptom onset was 3.8 months to first consultation, 8.0 months to diagnosis, 16.2 months to employment change (part-time/sick leave/retirement/unemployment), 17.5 months to use of a walking aid, 18.5 months to first occurrence of caregiver support, 22.8 months to use of a wheelchair, 24.6 months to use of a communication aid, 27.3 months to use of a respiratory aid, 28.6 months to use of gastrostomy feeding, 29.7 months to use of eye gaze technology and 30.3 months to entering a care facility. Multivariate analysis indicated significant effects of fast (versus slow) progression rate on time to reach all 11 milestones, as well as US (versus European) location, age, body mass index and bulbar onset (versus other) on time to reach milestones. Conclusions pALS rapidly reached clinical and disease-related milestones within 30 months from symptom onset. Milestones were reached significantly faster by pALS with fast versus slow progression. Geographic differences were observed.

Microbial metabolites in the gut‐brain axis of an amyotrophic lateral sclerosis model

Backgound Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by progressive atrophy of motor neurons. Recent studies have demonstrated gut microbiome-associated contributions to human ALS and ALS experimental mice SOD1­G93A. Treatment with dietary butyrate, a natural bacterial product, rectified intestinal abnormalities and reduced disease progression in ALS mice. The emergence of ALS as a multifactorial disorder is further emphasized by understanding gut-brain mechanisms such as microbial metabolites. Methods Here, we hypothesize that butyrate treatment increases the concentration of anti-inflammatory and neuroprotective metabolites. SOD1­G93A (G93A) mice were used as a model of human ALS. G93A and WT mice classified as treated and untreated groups. Treated groups were given 2% dietary butyrate in their drinking water while untreated were given water ad libitum. Fecal samples were collected at 4, 8 and 14 weeks of age for treated groups while samples for untreated groups were obtained at 4, 7,13, and 17 weeks of age. Metabolites in fecalsamples were prepared using the automated MicroLab STAR® system (Hamilton Company) and measured by Metabolon. Raw data were extracted, peak-identified and QC processed using Metabolon's hardware and software. Statistical comparisons between metabolite concentrations in untreated and treated groups were conducted using two-way ANOVA via R. Results In untreated G93A mice, there was an increase in indole derived metabolites at 13 weeks of age, at onset of ALS symptoms. Specifically, concentration of indole acetate and indole acrylate, which are known to be aryl hydrocarbon receptor (AhR) ligands which indirectly aid in neuroprotection, increased at 13 weeks. Additionally, endocannabinoid concentrations, such as behenoyl ethanolamide (BEA) increased at 13 weeks while linoleoyl ethanolamide (LigEA) increased at 17 weeks. Our results suggest that the increased production of anti-inflammatory and neuroprotective metabolites onset and at 17 weeks could be a compensatory mechanism by the gut to alleviate ALS pathology. We also identify specific microbial metabolites associated with ALS as well as investigate the effect of butyrate on metabolites over the course of disease. Conclusion This study profiled fecal metabolites in G93A mice at different stages of ALS and with butyrate treatment. Four metabolites emerged as metabolic markers with diagnostic potential. Our findings contribute to the notion that the gut microbiome may play an essential role in the pathogenesis and pathophysiology of ALS and have significant translational implications for identifying new biomarkers for ALS. Further investigation is needed to explore whether related genes or enzymes could elucidate biological mechanisms of how ALS develops at the systemic level.

Botulinum toxin for the treatment of lower limb cramp pain in patients with Amyotrophic Lateral Sclerosis

Background:&#x0D; Muscle cramps and pain associated with them can be seen in patients with amyotrophic lateral sclerosis (ALS) and are known to reduce the quality of life. Pharmacological treatment may not benefit all patients in treating these cramps. We assess the efficacy of Onabotulinum toxin A (BTX-A) in the treatment of lower limb cramps in patients with ALS.&#x0D; Methods:&#x0D; This retrospective chart review included a total of ten patients with ALS who suffered from pain due to lower limb cramps and were managed with BTX-A. Data including patient demographics, visual analog pain scale at different intervals during follow up, ALS functional rating scale and site of onset of ALS symptoms were documented. The pain score at baseline (before administration), at 3 months follow up and at 6 months follow up were compared using Wilcoxon test to assess BTX-A’s efficacy.&#x0D; Results:&#x0D; A significant improvement in average pain score due to cramps from baseline to the 6-month interval with a change of 3.1±0.7 (p&lt;0.05,95%CI) was seen on the pain scale. No adverse events were noted during administration or post injections.&#x0D; Conclusion:&#x0D; Local BTX-A administration is an efficacious and safe procedure for improving pain associated with cramps in patients with ALS.

Bidens pilosa Extract Administered after Symptom Onset Attenuates Glial Activation, Improves Motor Performance, and Prolongs Survival in a Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by progressive paralysis resulting from the death of upper and lower motor neurons. There is currently no effective pharmacological treatment for ALS, and the two approved drugs riluzole and edaravone have limited effects on the symptoms and only slightly prolong the life of patients. Therefore, the development of effective therapeutic strategies is of paramount importance. In this study, we investigated whether Miyako Island Bidens pilosa (MBP) can alleviate the neurological deterioration observed in a superoxide dismutase-1 G93A mutant transgenic mouse (G93A mouse) model of ALS. We orally administered 2 g/kg/day of MBP to G93A mice at the onset of symptoms of neurodegeneration (15 weeks old) until death. Treatment with MBP markedly prolonged the life of ALS model mice by approximately 20 days compared to that of vehicle-treated ALS model mice and significantly improved motor performance. MBP treatment prevented the reduction in SMI32 expression, a neuronal marker protein, and attenuated astrocyte (detected by GFAP) and microglia (detected by Iba-1) activation in the spinal cord of G93A mice at the end stage of the disease (18 weeks old). Our results indicate that MBP administered after the onset of ALS symptoms suppressed the inflammatory activation of microglia and astrocytes in the spinal cord of the G93A ALS model mice, thus improving their quality of life. MBP may be a potential therapeutic agent for ALS.

ROS-related mitochondrial dysfunction in skeletal muscle of an ALS mouse model during the disease progression.

In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction and oxidative stress form a vicious cycle that promotes neurodegeneration and muscle wasting. To quantify the disease-stage-dependent changes of mitochondrial function and their relationship to the generation of reactive oxygen species (ROS), we generated double transgenic mice (G93A/cpYFP) that carry human ALS mutation SOD1G93A and mt-cpYFP transgenes, in which mt-cpYFP detects dynamic changes of ROS-related mitoflash events at individual mitochondria level. Compared with wild type mice, mitoflash activity in the SOD1G93A (G93A) mouse muscle showed an increased flashing frequency prior to the onset of ALS symptom (at the age of 2 months), whereas the onset of ALS symptoms (at the age of 4 months) is associated with drastic changes in the kinetics property of mitoflash signal with prolonged full duration at half maximum (FDHM). Elevated levels of cytosolic ROS in skeletal muscle derived from the SOD1G93A mice were confirmed with fluorescent probes, MitoSOX™ Red and ROS Brite™570. Immunoblotting analysis of subcellular mitochondrial fractionation of G93A muscle revealed an increased expression level of cyclophilin D (CypD), a regulatory component of the mitochondrial permeability transition pore (mPTP), at the age of 4 months but not at the age of 2 months. Transient overexpressing of SOD1G93A in skeletal muscle of wild type mice directly promoted mitochondrial ROS production with an enhanced mitoflash activity in the absence of motor neuron axonal withdrawal. Remarkably, the SOD1G93A-induced mitoflash activity was attenuated by the application of cyclosporine A (CsA), an inhibitor of CypD. Similar to the observation with the SOD1G93A transgenic mice, an increased expression level of CypD was also detected in skeletal muscle following transient overexpression of SOD1G93A. Overall, this study reveals a disease-stage-dependent change in mitochondrial function that is associated with CypD-dependent mPTP opening; and the ALS mutation SOD1G93A directly contributes to mitochondrial dysfunction in the absence of motor neuron axonal withdrawal.

Dysregulation of Mitochondrial Permeability Transition Pore (MPTP) is Associated with Enhanced ROS Production in Skeletal Muscle of an ALS Mouse Model

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease. Oxidative stress is implicated in ALS pathophysiology. Using ROS Brite™ 570, a cytosolic ROS detector, we found a significant increase in ROS production of muscle fibers derived from the ALS G93A mice. Mitochondria are the major source of ROS production. In order to detect early changes in ROS-related mitochondrial metabolic function, we generated double transgenic mice (G93A/cpYFP) that carry human ALS mutation SOD1G93A and mt-cpYFP transgenes, in which mt-cpYFP monitors dynamic changes of ROS-related mitoflash events at the single mitochondrion level. Remarkably, G93A muscle cells show early and disease stage-dependent changes in mitoflash events. The mitoflash activity at the age of 2 months (before ALS symptom onset) is marked by an increased flashing area in G93A muscle fibers, while their kinetics properties remain unchanged. After ALS onset (3-month old), there are drastic changes in the kinetics of mitoflash signal with prolonged FDHM (full duration at half maximum) of the mitoflash signal. Thus, mitoflash provides a sensitive and quantitative biomarker for evaluating ROS-related mitochondrial dysfunction. It is known that uncontrolled opening of mitochondrial permeability transition pore (mPTP) is a key step to promote mitochondrial ROS production. While the molecular composition of mPTP is still incompletely understood, studies have shown that cyclophilin D (CypD) promotes the opening of mPTP and phosphorylated form of GSK-3β participates in maintaining mPTP in the closed state. We used subcellular fractionation to isolate mitochondria from skeletal muscle of G93A mice, and found an increased CypD expression level in muscle mitochondria, while the phosphorylated form of GSK-3β was significantly reduced in mitochondria of G93A muscle. Thus, both may act as triggering factors for mPTP opening in G93A muscle.

A model of recurrent concussion that leads to long-term motor deficits, CTE-like tauopathy and exacerbation of an ALS phenotype.

Concussion injury is the most common form of traumatic brain injury (TBI). How recurrent concussions alter long-term outcomes is poorly understood, especially as related to the development of neurodegenerative disease. We evaluated the functional and pathological consequences of repeated TBI over time in wild type (WT) rats as well as rats harboring the human SOD1 mutation ("SOD1"), a model of familial amyotrophic lateral sclerosis (ALS). A total of 42 rats, 26 WT and 16 SOD1, were examined over a study period of 25 weeks (or endpoint). At postnatal day 60, 20 WT and 7 SOD1 rats were exposed to mild, bilateral TBI once per week for either 2 weeks (2×TBI) or 5 weeks (5×TBI) using a controlled cortical impact device. Six WT and nine SOD1 rats underwent sham injury with anesthesia alone. Twenty WT rats were euthanized at 12 weeks after first injury and six WT rats were euthanized at 25 weeks after first injury. SOD1 rats were euthanized when they reached ALS disease endpoint. Weekly body weights and behavioral assessments were performed. Tauopathy in brain tissue was analyzed using immunohistochemistry. 2XTBI injured rats initially demonstrated recovery of motor function but failed to recover to baseline within the 12-week study period. Relative to both 2XTBI and sham controls, 5XTBI rats demonstrated significant deficits that persisted over the 12-week period. SOD1 5XTBI rats reached a peak body weight earlier than sham SOD1 rats, indicating earlier onset of the ALS phenotype. Histologic examination of brain tissue revealed that, in contrast with sham controls, SOD1 and WT TBI rats demonstrated cortical and corpus collosum thinning and tauopathy, which increased over time. Unlike previous models of repeat brain injury, which demonstrate only transient deficits in motor function, our concussion model of repeat, mild, bilateral TBI induced long-lasting deficits in motor function, decreased cortical thickness, shrinkage of the corpus callosum, increased brain tauopathy, and earlier onset of ALS symptoms in SOD1 rats. This model may allow for a greater understanding of the complex relationship between TBI and neurodegenerative diseases and provides a potential method for testing novel therapeutic strategies.

My memories are important to me: Changes in autobiographical memory in amyotrophic lateral sclerosis.

The loss of autobiographical memories (ABM) is a pervasive feature of neurodegenerative diseases. Studies to date have not investigated ABM retrieval in amyotrophic lateral sclerosis (ALS), a multisystem disorder that may be associated with cognitive dysfunction and dementia. The integrity of autobiographical memory was evaluated in 22 ALS patients compared with 28 age-matched controls using the Autobiographical Interview (AI), a semistructured interview assessing autobiographical events from discrete time periods across the life span. ABM retrieval was preserved in ALS and remained rich in detail for personal events in recent (last 12-months) and remote (teenage years) time epochs. ABM retrieval was positively correlated with months since ALS symptom onset, with a greater number of contextual details being recalled as ALS progressed. A shift in how ABMs were perceived in ALS patients became apparent, with more recurrent reflection of recent life, which was also weighted with greater personal importance. The preservation of ABM in ALS has clinical implications for the use of life review as a therapeutic tool in a multidisciplinary care setting. (PsycINFO Database Record

Glutamate release and uptake processes are altered in a new mouse model of amyotrophic lateral sclerosis.

In this paper, we showed that in the cortex of mice expressing an abberant form of FUS protein that model amyotrophic lateral sclerosis (ALS), the processes of KCl-induced and basal [(3)H]glutamate release and uptake are altered at the presymptomatic stage as compared to the non-transgenic littermates. The change in these three parameters in transgenic animals causes excitotoxicity, which, in turn, may lead to massive loss of motor neurons and the onset of ALS symptoms.

Type I Vs. Type II Cytokine Levels as a Function of SOD1 G93A Mouse Amyotrophic Lateral Sclerosis Disease Progression.

Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease that is characterized by the degradation of neurons throughout the central nervous system. Inflammation have been cited a key contributor to ALS neurodegeneration, but the timeline of cytokine upregulation remains unresolved. The goal of this study was to temporally examine the correlation between the varying levels of pro-inflammatory type I cytokines (IL-1β, IL-1α, IL-12, TNF-α, and GFAP) and anti-inflammatory type II cytokines (IL-4, IL-6, IL-10) throughout the progression of ALS in the SOD1 G93A mouse model. Cytokine level data from high copy SOD1 G93A transgenic mice was collected from 66 peer-reviewed studies. For each corresponding experimental time point, the ratio of transgenic to wild type (TG/WT) cytokine was calculated. One-way ANOVA and t-tests with Bonferonni correction were used to analyze the data. Meta-analysis was performed for four discrete stages: early, pre-onset, post-onset, and end stage. A significant increase in TG cytokine levels was found when compared to WT cytokine levels across the entire SOD1 G93A lifespan for majority of the cytokines. The rates of change of the individual cytokines, and type I and type II were not significantly different; however, the mean fold change of type I was expressed at significantly higher levels than type II levels across all stages with the difference between the means becoming more pronounced at the end stage. An overexpression of cytokines occurred both before and after the onset of ALS symptoms. The trend between pro-inflammatory type I and type II cytokine mean levels indicate a progressive instability of the dynamic balance between pro- and anti-inflammatory cytokines as anti-inflammatory cytokines fail to mediate the pronounced increase in pro-inflammatory cytokines. Very early immunoregulatory treatment is necessary to successfully interrupt ALS-induced neuroinflammation.

P94. Effects of non-invasive ventilation on sleep and nocturnal ventilation in patients with amyotrophic lateral sclerosis

The majority of patients with amyotrophic lateral sclerosis (ALS) develop chronic ventilatory failure which substantially adds to disease burden and massively affects prognosis. Both quality of life and life expectancy can be influenced by non-invasive ventilation (NIV). Initiation of NIV is indicated in case of sleep-disordered breathing (SDB), daytime hypercapnia, or significant diaphragmatic weakness. Since nocturnal hypercapnia and sleep apnea substantially reduce sleep quality we investigated the effects of NIV on objective measures of both sleep quality and ventilation in patients with ALS. We retrospectively analysed polysomnography (PSG) and oxycapnometry (OC) data obtained from patients with ALS in whom NIV was initiated based on the presence of SDB. PSG and OC were used in all patients for establishing the diagnosis of SDB (t0), for treatment initiation (t1) and for follow-up examination at 3, 9, and 15 months (t2, t3, and t4, respectively). As outcome parameters we chose sleep efficiency (SE), slow wave sleep percentage (N3), REM sleep percentage (REM), apnea hypopnea index (AHI), oxygen desaturation index (ODI), desaturation time (T < 90), respiratory rate (RR) and maximal nocturnal transcutaneous carbon dioxide tension (tc-CO2). Records from 62 patients were analysed. Mean age was 63.2 years, and mean disease duration was 23.1 months. 28 patients were female, and 22 patients reported bulbar onset of ALS symptoms. All patients were started on pressure and volume-controlled bilevel ventilation via a nasal or oronasal interface. Comparison of the above parameters at t0 and t1 showed significant improvement of AHI and ODI, oxygenation, CO2 elimination, and sleep stage duration (N3, REM) in the first night on NIV. Sleep efficiency was neither improved nor reduced by NIV. At t2, t3 and t4 the number of PSG records available became smaller because in many patients, follow-up studies included rather polygraphy than PSG (t2, 33 patients, t3, 15 patients, t4, 11 patients with PSG data). ANOVA for repeated measures revealed stable normoxia and eucapnia under bilevel ventilatory support. Objective measures of sleep quality did not show any significant change over time. Increasing duration of NIV per day was found in all patients in the course of the disease, reflecting disease progression. In patients with ALS, NIV initiation significantly improves objective sleep quality, oxygenation and CO2 elimination in the first night of treatment. Over time, NIV is able to warrant nocturnal normoventilation with only minor changes to ventilator settings. Objective sleep quality does not significantly change in the first 15 months after onset of NIV.

P95. REM sleep without atonia and REM sleep behavioral disorder in patients with amytrophic lateral sclerosis

REM sleep behavioral disorder (RBD) is characterized by dream-enacting behavior arising from REM sleep. On polysomnography (PSG), physiological muscle atonia is absent during phasic REM sleep in patients with RBD. RBD reflects disinhibition of cortical motor impulses on the brainstem level during REM sleep. RBD comprises a prodromal or concomitant condition in neurodegenerative diseases characterized by α-synuclein deposition. In patients with amyotrophic lateral sclerosis (ALS) RBD has not been systematically been investigated. Since neurodegeneration in ALS spreads from the motor cortex to the bulbar reticular formation we retrospectively studied the presence of REM sleep without atonia (RSWA) and RBD in patients with ALS. Patients with possible, probable or definite ALS according to the revised El Escorial criteria were included in the study. Occurrence of nocturnal behavioral abnormalities was assessed by a standardized physician interview. Exlusion criteria were tetraplegia, home ventilatory support, continous positive airway pressure support for obstructive sleep apnea, concomitant PD or MSA, dementia, and medication with either benzodiazepines or tricyclic antidepressants. Video polysomnography was performed according to standard recommendations, and PSG records were validated manually by two independent scorers according to the AASM criteria. Tonic muscle activity during REM sleep was scored when 50% ore more of a single 30 s epoch showed an EMG amplitude higher than the smallest EMG amplitude during non-REM sleep. Phasic muscle activity during REM sleep was scored when 5 out of 10 3 s mini-epochs showed transient muscle activity for 0.5–1.0 s with an EMG amplitude at least 4-fold above background activity. Classification of behavioral abnormalities during REM sleep was performed based on the widely used RBD severity scale (RBD-SS). Video-polysomnography records of 12 patients underwent detailed analysis. Three patients were female. Mean age was 48.8 years. One patient was diagnosed to have familial ALS with a proven mutation in the FUS gene. Two patients had bulbar onset of ALS symptoms. Behavioral abnormalities or increased motor acitivity during sleep clearly not associated with nocturnal dyspnea were reported by two patients and their bed partners. Subtle clinical signs of parkinsonism were present in only one of these patients on admission (mild hyposmia, distal rigor). Both patients showed dream-enacting behavior in combination with RSWA on video-PSG confirming RBD. Four patients without self-reported symptoms of possible RBD exhibited non-physiologic motor activity during REM sleep including jerks and vocalisations. Violent behavior or vigorous movements did not occur. 9 out of 12 patients showed tonic or phasic musle activity on surface EMG reflecting RSWA. It is not known whether ALS predisposes to the development of RBD. In accordance to very few case reports in the literature our study suggests that both RSWA and mild RBD may be encountered in patients with ALS. Further studies in larger patient samples are necessary to elucidate the prevalence of RBD in patients with ALS.

Amyotrophic Lateral Sclerosis survival analysis: Swallowing and non-oral feeding.

Dysphagia-related complications, such as aspiration pneumonia and malnutrition, are major causes of death among patients with Amyotrophic Lateral Sclerosis (ALS). To analyze clinical features associated with worsened swallowing and non-oral feeding in ALS. This is a long-term study of 33 ALS patients, who were observed between 2006 and 2011 in three month intervals. These subjects underwent Fiberoptic Endoscopic Evaluation of Swallowing and Functional Oral Intake Scale classification. Survival analysis was performed using Cox Regression. The worsening of swallowing functionality was more rapid in late-onset ALS patients (risk of 4% per year) and individuals with bulbar onset ALS (risk of 188% per year). Non-oral feeding was associated with both the later onset of ALS symptoms (risk of 7.5% per year) and shorter disease duration (risk of 13% per year). Worsened swallowing was more rapid in individuals who were older at symptoms onset and who had bulbar onset ALS. Non-oral feeding was associated with both age at symptoms onset and shorter disease duration.

Zinc transporters ZnT3 and ZnT6 are downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis.

The loss of homeostasis of essential metals is associated with various diseases, including neurodegenerative diseases. Previous studies have shown that the levels of zinc (Zn) are significantly higher in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Zn transporters and metallothioneins tightly control intracellular and extracellular Zn levels. This study investigated the protein levels of ZnT, a Zn transporter family, in ALS patients and model mice. The mRNA expression of ZnT1, -3, -4, -5, -6, -7, and -10 was assessed in the spinal cords of human control subjects. ZnT3 and ZnT6 protein levels were significantly diminished in the spinal cords of sporadic ALS patients compared with controls. Furthermore, immunohistochemical staining demonstrated decreased ZnT3 and ZnT6 immunoreactivity in the ventral horn of the spinal cords in ALS patients. Moreover, immunohistochemical analysis revealed that all ZnTs expressed in the spinal cords were localized in a distinct subset of motor neurons. In addition, ZnT3 and ZnT6 protein levels were not altered in SOD1 (G93A) mutant transgenic mice before or after the onset of ALS symptoms compared with controls. These results suggest that ZnT3 and ZnT6 protein levels are decreased in the spinal cords of sporadic ALS patients; however, this did not occur merely via loss of motor neurons.

Amyotrophic lateral sclerosis after embolization of cerebral arterioveneous malformations

Cerebral arterioveneous malformations (AVM) can cause neurological symptoms and carry a risk of hemorrhage. Therapeutic options to cure or reduce AVM include surgery, embolization, irradiation, and combinations thereof. Prompted by three index cases treated in our center, we studied whether AVM embolization is associated with an increased risk of subsequent amyotrophic lateral sclerosis (ALS). In a monocenter series, we retrospectively analyzed the new development of ALS in patients who had been treated with embolization of cerebral AVM from 1986 to 2010 (n = 1,114). After a median follow-up of 11 years (range, 0-25 years) after first embolization, seven patients developed ALS with a median latency of 14 years (range, 12-17 years) and a median age of ALS onset of 38 years (range, 28-52 years). In all cases, the initial limb of ALS symptom onset was ipsilateral to the AVM. Five patients died within the follow-up period, with a range of 1-4 years after the onset of ALS symptoms. The seven patients belonged to a subgroup of 34 patients who had in common a rare AVM architecture characterized by significant perinidal angiogenesis. All cases were partially treated by at least three embolization sessions. As there is no known association between AVM and ALS, AVM embolization must be taken into account to have contributed to the development of ALS in the seven patients with this rare AVM architecture. Searching for underlying mechanisms, we compared frozen serum samples that were available from four of the patients who developed ALS, from eight patients with AVM of other architecture, and less than three embolizations who did not develop ALS, and of 20 controls. The concentration of vascular endothelial growth factor (VEGF) in the serum was lowest in AVM patients who developed ALS (245 ± 154 pmol/l) and highest in controls (409 ± 178 pmol/l). Although this difference was not statistically significant in the small sample, it suggests that low VEGF production by AVM with significant angiogenesis, possibly due to multiple embolization procedures, might have contributed to ALS development. ALS should be considered as a late complication of multiple embolizations of cerebral AVM characterized by significant perinidal angiogenesis.

Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial

In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease. In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18-80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice-interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12-18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189. Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441·76, 95% CI 415·43-468·08) and those in the placebo group (438·84, 412·81-464·88; p=0·86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (-13·34 in the dexpramipexole group vs -13·42 in the placebo group; p=0·90) or time to death (74 [16%] vs 79 [17%]; hazard ratio 1·03 [0·75-1·43]; p=0·84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups. Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis. Biogen Idec.

Limb-onset amyotrophic lateral sclerosis patients visiting orthopedist show a longer time-to-diagnosis since symptom onset

BackgroundThere have been several reports concerning the survival time after symptom onset in patients with amyotrophic lateral sclerosis (ALS). However, little is known about how the choice of physician (i.e., general practitioner, neurologist, etc.) may affect the time it takes for a diagnosis of ALS to be made.MethodsWe conducted a retrospective study, covering a 20-year period, comparing the type of physician first consulted by an ALS patient at the time of initial symptoms and the amount of time that elapsed to the final diagnosis of ALS. A total of 202 patients were diagnosed and stratified according to the onset of ALS symptoms (bulbar onset [BO] and limb onset [LO]). We noted the type of physician first seen by the patient. The diagnostic interval was calculated as the time between onset of symptoms and the final diagnosis of ALS.ResultsA total of 202 ALS patients were examined. Clinical BO and LO was observed in 78 (36.6%) and in 124 (61.4%) of these patients, respectively. The type of physician examining these patients at the first symptoms of disease was as follows (BO and LO): neurologist (38.5% and 25.8%), general practitioner (14.1% and 35.5%), orthopedist (12.8% and 35.5%), otolaryngologist (15.4% and 0%), and neurosurgeon (14.1% and 3.2%). Mean diagnostic interval (standard deviation) for patients with either set of symptoms was 13.1 (6.5) months; the diagnostic interval of patients with BO and LO was 9.2 (4.5) and 15.2 (7.7) months, respectively. ALS diagnosis in LO patients was delayed by more than 10 months when the patient first consulted an orthopedist rather than a neurologist.ConclusionMore than 50% of the ALS patients included in this study did not visit a neurologist at the first symptoms of disease onset. The diagnosis of ALS was prolonged in LO patients visiting an orthopedist. We speculate that this increase in the diagnostic interval in LO patients visiting an orthopedist was due to a lack of bulbar symptoms in the early stages of this disease.

Amyotrophic Lateral Sclerosis-Like Conditions in Possible Association with Cholesterol-Lowering Drugs

While cases of amyotrophic lateral sclerosis (ALS) or ALS-like conditions have arisen in apparent association with HMG-CoA reductase inhibitors ('statins') and/or other lipid-lowering drugs (collectively termed 'statins' in this paper for brevity), additional information is needed to understand whether the connection may be causal. The University of California, San Diego (UCSD) Statin Effects Study is a patient-targeted adverse event surveillance project focused on lipid-lowering agents, whose aim is to capitalize on patient reporting to further define characteristics and natural history of statin adverse effects (AEs), and to ascertain whether a patient-targeted surveillance system might lead to presumptive identification of previously unrecognized AEs. ALS was a candidate 'new' AE identified through this process. The aim of the analysis presented here was to examine characteristics and natural history of reported statin-associated ALS-like conditions with attention to factors that may bear on the issue of causality. For the present analysis, we focused on cases of statin-associated ALS that were reported to our study group prior to publication of a possible statin-ALS association. Of 35 identified subjects who had contacted the UCSD Statin Effects Study group to report ALS or an ALS-like condition, 18 could not be reached (e.g. contact information was no longer valid). Six were unable to participate (e.g. due to progression of their disease). Of the 11 who could be contacted and were able to participate, one declined to give informed consent. The remaining ten, with either a formal or probable diagnosis of ALS in the context of progressive muscle wasting/weakness arising in association with lipid-lowering drug therapy, completed a mail or phone survey eliciting information about ALS symptom onset and change in association with drug use/modification and development of statin-associated AEs. We reviewed findings in the context of literature on statin antioxidant/pro-oxidant balance, as well as ALS mechanisms involving oxidative stress and mitochondrial dysfunction. All ten subjects reported amelioration of symptoms with drug discontinuation and/or onset or exacerbation of symptoms with drug change, rechallenge or dose increase. Three subjects initiated coenzyme Q10 supplementation; all reported initial benefit. All subjects reportedly developed statin AEs (not indicative of ALS) prior to ALS symptom onset, strongly disproportionate to expectation (p < 0.001). Since this reflects induction of pro-oxidant effects from statins, these findings lend weight to a literature-supported mechanism by which induction by statins of oxidative stress with amplification of mitochondrial dysfunction, arising in a vulnerable subgroup, may propel mechanisms underlying both AEs and, more rarely, ALS. A theoretical foundation and preliminary clinical observations suggest that statins (and other lipid-lowering drugs) may rarely be associated with ALS in vulnerable individuals in whom pro-oxidant effects of statins predominate. Our observations have explanatory relevance extending to ALS causes that are not statin associated and to statin-associated neurodegenerative conditions that are not ALS. They suggest means for identification of a possible vulnerable subgroup. Indeed whether statins may, in contrast, confer ALS protection when antioxidant effects predominate merits examination.