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Sample records for amyotrophic lateral sclerosis

  1. ALS (Amyotrophic Lateral Sclerosis)

    Science.gov (United States)

    ... here Home » Disorders » Patient & Caregiver Education » Fact Sheets Amyotrophic Lateral Sclerosis (ALS) Fact Sheet What is amyotrophic lateral sclerosis? Who ... Where can I get more information? What is amyotrophic lateral sclerosis? Amyotrophic lateral sclerosis (ALS) is a group of ...

  2. Amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Leigh P Nigel

    2009-02-01

    Full Text Available Abstract Amyotrophic lateral sclerosis (ALS is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year and prevalence (average 5.2 per100,000 are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio~1.5:1. Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1–2 years. Paralysis is progressive and leads to death due to respiratory failure within 2–3 years for bulbar onset cases and 3–5 years for limb onset ALS cases. Most ALS cases are sporadic but 5–10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2–5% have mutations of the TARDBP (TDP-43 gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43

  3. Juvenile amyotrophic lateral sclerosis.

    Science.gov (United States)

    Aggarwal, Anju; Shashiraj

    2006-03-01

    Juvenile amytrophic lateral sclerosis (JALS) is a type of motor neuron disease presenting before 25 years of age. It is characterized by a combination of upper and lower motor signs. It may be familial or sporadic. We are reporting a sporadic case of JALS with onset of symptoms at 4 years of age. Diagnostic criteria and a brief review of literature are presented.

  4. Clinical neurogenetics: amyotrophic lateral sclerosis.

    Science.gov (United States)

    Harms, Matthew B; Baloh, Robert H

    2013-11-01

    Our understanding of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is expanding rapidly as its genetic causes are uncovered. The pace of new gene discovery over the last 5 years has accelerated, providing new insights into the pathogenesis of disease and highlighting biological pathways as targets for therapeutic development. This article reviews our current understanding of the heritability of ALS and provides an overview of each of the major ALS genes, highlighting their phenotypic characteristics and frequencies as a guide for clinicians evaluating patients with ALS. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Depression in amyotrophic lateral sclerosis

    Science.gov (United States)

    ATASSI, NAZEM; COOK, AMANDA; PINEDA, CRISTIANA M. E.; YERRAMILLI-RAO, PADMAJA; PULLEY, DARLENE; CUDKOWICZ, MERIT

    2011-01-01

    Depression is an under-recognized comorbidity associated with amyotrophic lateral sclerosis (ALS). The goals of this study were to prospectively estimate the prevalence of depression and other ALS related symptoms and to study the impact of depression on enrollment in research studies. One hundred and twenty-seven people with ALS completed the ALS Depression Inventory (ADI-12) and answered questions about ALS related symptoms and research study enrollment preferences. Demographics, ALS symptoms, medications, functional status, and research enrollment were compared between depressed and non-depressed patients. Results showed that the prevalence of mild and severe depression was 29% and 6%, respectively. More than one-third of our ALS patients were receiving anti-depressants to treat depression, sialorrhea, and pseudobulbar affect. Depression prevalence was not correlated with disease duration or progression. Except for anxiety, none of the ALS related symptoms predicted depression. The presence of depression did not have an effect on the decision to enroll in research studies. In conclusion, major depression is less common in our ALS cohort than in the general population. The diagnosis of depression can be masked by some ALS related symptoms and it has no impact on enrollment in ALS clinical trials. PMID:21091399

  6. Respiratory treatment of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Benditt, Joshua O; Boitano, Louis

    2008-08-01

    Amyotrophic lateral sclerosis is a progressive neurodegenerative disease with no known cure. The major cause of mortality and major morbidities is related to the effects of the disease on the muscles of the respiratory system (ie, the inspiratory, expiratory, and upper airway muscles). Dyspnea, swallowing difficulties, sialorrhea, and impaired cough are all symptoms that can be palliated through pharmacologic and nonpharmacologic means. Noninvasive positive pressure ventilation, in particular, is a technique that not only relieves dyspnea but may also extend the lives of patients who have this disease. It should be offered to all patients who have amyotrophic lateral sclerosis with a forced vital capacity of less than 50 percent.

  7. Towards gene therapy in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Wisman, Liselijn Agatha Barendina

    2004-01-01

    Amyotrophic lateral sclerosis (ALS) is a paralytic neurodegenerative disorder, characterised by a specific loss of motoneurons. Although the exact pathogenesis is largely enigmatic, it is known that glutamate excitotoxicity plays an important role in motoneuron cell death. Glutamate is one of the

  8. Immune system alterations in amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Hovden, H; Frederiksen, J L; Pedersen, S W

    2013-01-01

    Amyotrophic lateral sclerosis is a disease of which the underlying cause and pathogenesis are unknown. Cumulatative data clearly indicates an active participation by the immune system in the disease. An increasingly recognized theory suggests a non-cell autonomous mechanism, meaning that multiple...

  9. Clinical psychology and amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Francesco Pagnini

    2010-07-01

    Full Text Available Amyotrophic Lateral Sclerosis is a fatal and progressive disease, characterized by progressive muscles weakness, with consequent loss of physical capacities. Psychologists can play an important role in ALS care, by providing clinical activities in every step of the disease, including support and counseling activities directed to patients, their caregivers and to physicians.

  10. Quantitative muscle ultrasonography in amyotrophic lateral sclerosis.

    NARCIS (Netherlands)

    Arts, I.M.P.; Rooij, F.G. van; Overeem, S.; Pillen, S.; Janssen, H.M.; Schelhaas, H.J.; Zwarts, M.J.

    2008-01-01

    In this study, we examined whether quantitative muscle ultrasonography can detect structural muscle changes in early-stage amyotrophic lateral sclerosis (ALS). Bilateral transverse scans were made of five muscles or muscle groups (sternocleidomastoid, biceps brachii/brachialis, forearm flexor group,

  11. Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis).

    Science.gov (United States)

    Jawdat, Omar; Statland, Jeffrey M; Barohn, Richard J; Katz, Jonathan S; Dimachkie, Mazen M

    2015-11-01

    Amyotrophic lateral sclerosis (ALS), a rapidly progressive, invariably fatal disease, involves mixed upper and lower motor neurons in different spinal cord regions. Patients with bulbar onset progress more rapidly than patients with limb onset or with a lower motor neuron presentation. Recent descriptions of regional variants suggest some patients have ALS isolated to a single spinal region for many years, including brachial amyotrophic diplegia, leg amyotrophic diplegia, and isolated bulbar palsy. Clearer definitions of regional variants will have implications for prognosis, understanding the pathophysiology of ALS, identifying genetic factors related to slower disease progression, and future planning of clinical trials. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. The management of amyotrophic lateral sclerosis.

    LENUS (Irish Health Repository)

    Phukan, Julie

    2009-02-01

    The terms amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) refer to a condition characterized by motor system degeneration with relative preservation of other pathways. Although there have been advances in symptomatic treatment, ALS remains an incurable condition. Advances in ALS management prolong survival but simultaneously raise challenging ethical dilemmas for physicians, patients and their families. Here, we review current practice in the management of ALS including pharmacological treatment, nutritional management, respiratory care, and evolving strategies in the management of cognitive impairment.

  13. Deontological aspects of the amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    T. M. Alekseeva

    2017-01-01

    Full Text Available One of the significant problems in deontology is the degree of awareness of terminally ill patients regarding the diagnosis and prognosis of their disease. This topic is complex and relevant, it touches ethical and psychological, legal and medical aspects. The article discusses the positive and negative aspects of fully informing patients  with amyotrophic lateral sclerosis about the fatal diagnosis. There are 2  clinical cases reflecting different approaches of this complex issue: full awareness and concealment of the diagnosis.

  14. Respiratory complications of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Benditt, Joshua O

    2002-06-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with no known cure. Involvement of muscles of the respiratory system, the inspiratory, expiratory, and upper airway muscles, is the major cause of morbidity and mortality. Dyspnea, swallowing difficulties, sialorrhea, and impaired cough are all symptoms that can be palliated with pharmacological and nonpharmacological methods. Noninvasive positive pressure ventilation (NPPV) in particular is a technique to assist ventilation that not only relieves dyspnea and ameliorates respiratory failure but may also extend the lives of patients with this disease. It should be offered to all ALS patients with a forced vital capacity of less than 50%.

  15. The changing scene of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Robberecht, Wim; Philips, Thomas

    2013-04-01

    Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.

  16. Amyotrophic lateral sclerosis: one or multiple causes?

    Science.gov (United States)

    Bastos, Aline Furtado; Orsini, Marco; Machado, Dionis; Mello, Mariana Pimentel; Nader, Sergio; Silva, Júlio Guilherme; da Silva Catharino, Antonio M.; de Freitas, Marcos R.G.; Pereira, Alessandra; Pessoa, Luciane Lacerda; Sztajnbok, Flavio R.; Leite, Marco Araújo; Nascimento, Osvaldo J.M.; Bastos, Victor Hugo

    2011-01-01

    The Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease in the adulthood, and it is characterized by rapid and progressive compromise of the upper and lower motor neurons. The majority of the cases of ALS are classified as sporadic and, until now, a specific cause for these cases still is unknown. To present the different hypotheses on the etiology of ALS. It was carried out a search in the databases: Bireme, Scielo and Pubmed, in the period of 1987 to 2011, using the following keywords: Amyotrophic lateral sclerosis, motor neuron disease, etiology, causes and epidemiology and its similar in Portuguese and Spanish. It did not have consensus as regards the etiology of ALS. Researches demonstrates evidences as regards intoxication by heavy metals, environmental and occupational causes, genetic mutations (superoxide dismutase 1), certain viral infections and the accomplishment of vigorous physical activity for the development of the disease. There is still no consensus regarding the involved factors in the etiology of ALS. In this way, new research about these etiologies are necessary, for a better approach of the patients, promoting preventive programs for the disease and improving the quality of life of the patients. PMID:21785676

  17. Amyotrophic lateral sclerosis: one or multiple causes?

    Directory of Open Access Journals (Sweden)

    Aline Furtado Bastos

    2011-04-01

    Full Text Available The Amyotrophic lateral sclerosis (ALS is the most common form of motor neuron disease in the adulthood, and it is characterized by rapid and progressive compromise of the upper and lower motor neurons. The majority of the cases of ALS are classified as sporadic and, until now, a specific cause for these cases still is unknown. To present the different hypotheses on the etiology of ALS. It was carried out a search in the databases: Bireme, Scielo and Pubmed, in the period of 1987 to 2011, using the following keywords: Amyotrophic lateral sclerosis, motor neuron disease, etiology, causes and epidemiology and its similar in Portuguese and Spanish. It did not have consensus as regards the etiology of ALS. Researches demonstrates evidences as regards intoxication by heavy metals, environmental and occupational causes, genetic mutations (superoxide dismutase 1, certain viral infections and the accomplishment of vigorous physical activity for the development of the disease. There is still no consensus regarding the involved factors in the etiology of ALS. In this way, new research about these etiologies are necessary, for a better approach of the patients, promoting preventive programs for the disease and improving the quality of life of the patients.

  18. Amyotrophic lateral sclerosis disease progression model.

    Science.gov (United States)

    Gomeni, Roberto; Fava, Maurizio

    2014-03-01

    Our objective was to develop: 1) a longitudinal model to describe amyotrophic lateral sclerosis (ALS) disease progression using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R); and 2) a probabilistic model to estimate the presence of clusters of trajectories in ALS progression over 12 months of treatment. Three hundred and thirty-eight patients treated with placebo from the PRO-ACT database were included in the analyses. A non-linear Weibull model best described the ALS disease progression, and a stepwise logistic regression approach was used to select the variables predicting a slow or fast disease progression. Results identified two clusters of trajectories: 1) slow disease progressors (46% of patients with a change from baseline of 13%); 2) fast disease progressors (54% of patients with a change from baseline of 49%). ROC curve analysis estimated the optimal cut-off for classifying patients as slow or fast disease progressors given ALSFRS-R measurements at 2-4 weeks. Results showed that the degree of ALS disease progression quantified by the ALSFRS-R symptomatic change on placebo is highly heterogeneous. In conclusion, this finding indicates the potential interest of disease progression models for implementing a population enrichment strategy to control the level of heterogeneity in the patients included in new trials.

  19. Motoneuron firing in amyotrophic lateral sclerosis (ALS

    Directory of Open Access Journals (Sweden)

    Mamede eDe Carvalho

    2014-09-01

    Full Text Available Amyotrophic lateral sclerosis is an inexorably progressive neurodegenerative disorder involving the classical motor system and the frontal effector brain, causing muscular weakness and atrophy, with variable upper motor neuron signs and often an associated fronto-temporal dementia. The physiological disturbance consequent on the motor system degeneration is beginning to be well understood. In this review we describe aspects of the motor cortical, neuronal and lower motor neuron dysfunction. We show how studies of the changes in the pattern of motor unit firing help delineate the underlying pathophysiological disturbance as the disease progresses. Such studies are beginning to illuminate the underlying disordered pathophysiological processes in the disease, and are important in designing new approaches to therapy and especially for clinical trials.

  20. Amyotrophic lateral sclerosis associated with pregnancy.

    LENUS (Irish Health Repository)

    Tyagi, A

    2012-02-03

    Amyotrophic lateral sclerosis (ALS) is the most common, progressive motor neurone disease but is rare in the obstetric population. Only 4 cases have been described in the English literature since 1975. We describe a 29 year old woman who presented with ataxia, lower limb weakness and dysarthria 4 weeks after the birth of her first child. The symptoms had onset during the pregnancy but had not been considered remarkable. There were clinical features of upper and lower motor neurone involvement without any sensory loss. MRI of brain and spine was normal. CSF analysis was negative. EMG studies confirmed the presence of widespread anterior horn cell dysfunction compatible with ALS. The patient was commenced on Riluzole and has progressed clinically, at 12 months post diagnosis.

  1. Risk factors for amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Ingre C

    2015-02-01

    Full Text Available Caroline Ingre,1 Per M Roos,2 Fredrik Piehl,1 Freya Kamel,3 Fang Fang4 1Department of Clinical Neuroscience, 2Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 3Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA; 4Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Abstract: Amyotrophic lateral sclerosis (ALS is the most common motor neuron disease. It is typically fatal within 2–5 years of symptom onset. The incidence of ALS is largely uniform across most parts of the world, but an increasing ALS incidence during the last decades has been suggested. Although recent genetic studies have substantially improved our understanding of the causes of ALS, especially familial ALS, an important role of non-genetic factors in ALS is recognized and needs further study. In this review, we briefly discuss several major genetic contributors to ALS identified to date, followed by a more focused discussion on the most commonly examined non-genetic risk factors for ALS. We first review factors related to lifestyle choices, including smoking, intake of antioxidants, physical fitness, body mass index, and physical exercise, followed by factors related to occupational and environmental exposures, including electromagnetic fields, metals, pesticides, β-methylamino-L-alanine, and viral infection. Potential links between ALS and other medical conditions, including head trauma, metabolic diseases, cancer, and inflammatory diseases, are also discussed. Finally, we outline several future directions aiming to more efficiently examine the role of non-genetic risk factors in ALS. Keywords: amyotrophic lateral sclerosis, risk factors, genetics, lifestyle, environment

  2. Randomized Sequential Trial of Valproic Acid in Amyotrophic Lateral Sclerosis

    NARCIS (Netherlands)

    Piepers, Sanne; Veldink, Jan H.; de Jong, Sonja W.; van der Tweel, Ingeborg; van der Pol, W.-Ludo; Uijtendaal, Esther V.; Schelhaas, H. Jurgen; Scheffer, Hans; de Visser, Marianne; de Jong, J. M. B. Vianney; Wokke, John H. J.; Groeneveld, Geert Jan; van den Berg, Leonard H.

    2009-01-01

    Objective: To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design. Methods:

  3. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

    DEFF Research Database (Denmark)

    McLaughlin, Russell L; Schijven, Dick; van Rheenen, Wouter

    2017-01-01

    We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide assoc......We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome...

  4. Modelling amyotrophic lateral sclerosis: progress and possibilities

    Directory of Open Access Journals (Sweden)

    Philip Van Damme

    2017-05-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a neurodegenerative disorder that primarily affects the motor system and presents with progressive muscle weakness. Most patients survive for only 2-5 years after disease onset, often due to failure of the respiratory muscles. ALS is a familial disease in ∼10% of patients, with the remaining 90% developing sporadic ALS. Over the past decade, major advances have been made in our understanding of the genetics and neuropathology of ALS. To date, around 20 genes are associated with ALS, with the most common causes of typical ALS associated with mutations in SOD1, TARDBP, FUS and C9orf72. Advances in our understanding of the genetic basis of ALS have led to the creation of different models of this disease. The molecular pathways that have emerged from these systems are more heterogeneous than previously anticipated, ranging from protein aggregation and defects in multiple key cellular processes in neurons, to dysfunction of surrounding non-neuronal cells. Here, we review the different model systems used to study ALS and discuss how they have contributed to our current knowledge of ALS disease mechanisms. A better understanding of emerging disease pathways, the detrimental effects of the various gene mutations and the causes underlying motor neuron denegation in sporadic ALS will accelerate progress in the development of novel treatments.

  5. Redox Regulation in Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Sonam Parakh

    2013-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS.

  6. GENETIC FACTORS ASSOCIATED WITH AMYOTROPHIC LATERAL SCLEROSIS

    Directory of Open Access Journals (Sweden)

    Katarina Vrabec

    2015-10-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a rare complex neurodegenerative disease characterized by degeneration of motor neurons in the cerebral cortex, brainstem and spinal cord. The disease mainly occurs in adults, typically between 50. and 60. years and presents with symptoms like muscular weakness, atrophy and later on paralysis which lead to death due to respiratory failure within 2-5 years from onset and remains incurable. The symptoms typically start in the muscles of arms or legs (spinal onset or bulbary (bulbar onset. Most ALS cases are sporadic although about 5% are familiar. Genetic factors contribute to the disease in sporadic form as well as in familial form. Mutations have been found in 116 genes among which SOD1, TARDBP, FUS and C9ORF72 are represented in highest frequencies. Besides those four genes we are also describing 13 other genes involved in the disease process. Oligogenic model has been proposed for ALS that considers mutations in two or more genes in one patient. We emphasize the convergence between hereditary and sporadic form, which are clinically inseparable, and other neurodegenerative diseases that share with ALS genetic and clinical characteristics. Because about 2/3 of familial cases and only about 11% of sporadic cases are explained by mutations the research have been aimed at discovering new candidate genes using  genome –wide association studies and at the epigenetic causes of the disease. We have recently completed the first representative genetic analysis of patients with ALS in Slovenia and research on methylation and microRNAs is currently in progress.

  7. Motor neuron disease (amyotrophic lateral sclerosis) arising from longstanding primary lateral sclerosis

    NARCIS (Netherlands)

    Bruyn, R. P.; Koelman, J. H.; Troost, D.; de Jong, J. M.

    1995-01-01

    Three men were initially diagnosed as having primary lateral sclerosis (PLS), but eventually developed amyotrophic lateral sclerosis (ALS) after 7.5, 9, and at least 27 years. Non-familial ALS and PLS might be different manifestations of a single disease or constitute completely distinct entities.

  8. Amyotrophic Lateral Sclerosis and Multiple Sclerosis Overlap: A Case Report

    Directory of Open Access Journals (Sweden)

    Francesca Trojsi

    2012-01-01

    Full Text Available The concurrence of amyotrophic lateral sclerosis (ALS and multiple sclerosis (MS is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI and cerebrospinal fluid (CSF analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS. This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear.

  9. Amyotrophic Lateral Sclerosis (ALS and Adenosine Receptors

    Directory of Open Access Journals (Sweden)

    Ana M. Sebastião

    2018-04-01

    Full Text Available In the present review we discuss the potential involvement of adenosinergic signaling, in particular the role of adenosine receptors, in amyotrophic lateral sclerosis (ALS. Though the literature on this topic is not abundant, the information so far available on adenosine receptors in animal models of ALS highlights the interest to continue to explore the role of these receptors in this neurodegenerative disease. Indeed, all motor neurons affected in ALS are responsive to adenosine receptor ligands but interestingly, there are alterations in pre-symptomatic or early symptomatic stages that mirror those in advanced disease stages. Information starts to emerge pointing toward a beneficial role of A2A receptors (A2AR, most probably at early disease states, and a detrimental role of caffeine, in clear contrast with what occurs in other neurodegenerative diseases. However, some evidence also exists on a beneficial action of A2AR antagonists. It may happen that there are time windows where A2AR prove beneficial and others where their blockade is required. Furthermore, the same changes may not occur simultaneously at the different synapses. In line with this, it is not fully understood if ALS is a dying back disease or if it propagates in a centrifugal way. It thus seems crucial to understand how motor neuron dysfunction occurs, how adenosine receptors are involved in those dysfunctions and whether the early changes in purinergic signaling are compensatory or triggers for the disease. Getting this information is crucial before starting the design of purinergic based strategies to halt or delay disease progression.

  10. [The symptomatic treatment of amyotrophic lateral sclerosis].

    Science.gov (United States)

    van den Berg, L H; van den Berg, J P; Mathus-Vliegen, E M; Kampelmacher, M J; van Kesteren, R G; Jennekens, F G

    2004-03-13

    Patients with amyotrophic lateral sclerosis (ALS) have symptoms of progressive muscle weakness, of disturbed speech and swallowing, and in the terminal phase those of respiratory weakness. Treatment options, in particular those for excessive weight loss and respiratory weakness, should be introduced to the patients and their families when the patient is emotionally capable and before dysarthria severely hampers communication. Special equipment for keeping the patient as mobile as possible should be made available much earlier than in the case of other diseases of the muscles as in ALS progression is much faster. Cramps, pathological crying or laughter, spasms, and spasticity can all be treated by medication. When speech can no longer be understood, adaptive strategies such as sign language, mime, posture and communication apparatus varying from a note pad to advanced computer systems can be used. Sialorrhoea, caused by difficulty swallowing with its accompanying danger of aspiration can be halted by the use of medication, by radiotherapy and by the injection into the salivary glands of botulin A toxin. Weight loss, also a result of dysphagia, can be avoided by eating frequent small meals or if necessary performing a percutaneous endoscopic or radiological gastroscopy. Excess mucus in the respiratory tract can be treated with anticholinergics. Difficulty in coughing up thick and sticky mucus cannot always be adequately helped. Respiratory weakness is treatable by external respiratory supportive therapy using a nasal mask, as well as invasive respiratory support via a trachcostoma and by treating the symptoms of respiratory weakness. The latter form of treatment is palliative and forms part of terminal care. During the terminal phase restlessness, anxiety, pain, and dyspnoea require the most attention. Treatment requires careful multidisciplinary cooperation.

  11. Amyotrophic Lateral Sclerosis, A Neuropathological Study

    Directory of Open Access Journals (Sweden)

    Geysu Karlıkaya

    2005-02-01

    Full Text Available Scientific Background: Amyotrophic lateral sclerosis (ALS is a neurodejenerative disorder of unknown cause characterized by degeneration and death of motor neurons. The diagnosis requires clinical evidence of both upper and lower motor neuron dysfunction and diagnostic tests to exclude other disorders with similar symptomatology. Pathologically ALS is characterized by loss of motor nerve cells in the spinal cord, brainstem and primary motor cortex accompanied by degeneration of the corticospinal tracts. A variety of inclusions have been described as major pathological features in ALS and other neurodegenerative disorders, these inclusions clarify the diagnosis and can provide insight into biochemical pathways leading to cell death. Objectives: This study is a review of the clinical and neuropathological features of sporadic ALS with special attention on two of the most common inclusions; Bunina bodies and ubiquitin immuonreactive (ub-ir inclusions. Material and Methods: We retrospectively analysed the clinical features of 11 autopsy confirmed ALS patients and classified the patients according to the revised El Escorial criteria. We also evaluated the motor cortex, hypoglossal nucleus and spinal cord sections from autopsies of these ALS patients and 7 controls, focusing on the specificity of Bunina bodies and ub-ir inclusions. Results: 4 patients qualified for clinically probable ALS, 1 patient for clinically probable-laboratory supported ALS, 5 patients for progressive spinal muscular atrophy and 1 patient for progressive bulbar palsy. Both Bunina bodies and ub-ir inclusions were found in most of these cases, %81.8 and %90.9 respectively. No Bunina bodies were seen in the control cases while ub-ir inclusions were seen in 3 control cases. Conclusions: This study confirms the specificity of Bunina bodies in sporadic ALS. Since ub-ir inclusions were also seen in a few of the controls, although they are characteristic of sporadic ALS they are not

  12. Mortality, health, social and economic consequences of amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Jennum, Poul; Ibsen, Rikke Falkner; Pedersen, Stephen Wørlich

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that imposes a great burden on the patient, the patient's family and society. However, we lack information about the total disease burden at a national level, especially regarding costs before and after diagnosis and the con......Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that imposes a great burden on the patient, the patient's family and society. However, we lack information about the total disease burden at a national level, especially regarding costs before and after diagnosis...

  13. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Kenna, Kevin P; van Doormaal, Perry T C; Dekker, Annelot M; Ticozzi, Nicola; Kenna, Brendan J; Diekstra, Frank P; van Rheenen, Wouter; van Eijk, Kristel R; Jones, Ashley R; Keagle, Pamela; Shatunov, Aleksey; Sproviero, William; Smith, Bradley N; van Es, Michael A; Topp, Simon D; Kenna, Aoife; Miller, Jack W; Fallini, Claudia; Tiloca, Cinzia; McLaughlin, Russell L; Vance, Caroline; Troakes, Claire; Colombrita, Claudia; Mora, Gabriele; Calvo, Andrea; Verde, Federico; Al-Sarraj, Safa; King, Andrew; Calini, Daniela; de Belleroche, Jacqueline; Baas, Frank; van der Kooi, Anneke J; de Visser, Marianne; Ten Asbroek, Anneloor L M A; Sapp, Peter C; McKenna-Yasek, Diane; Polak, Meraida; Asress, Seneshaw; Muñoz-Blanco, José Luis; Strom, Tim M; Meitinger, Thomas; Morrison, Karen E; Lauria, Giuseppe; Williams, Kelly L; Leigh, P Nigel; Nicholson, Garth A; Blair, Ian P; Leblond, Claire S; Dion, Patrick A; Rouleau, Guy A; Pall, Hardev; Shaw, Pamela J; Turner, Martin R; Talbot, Kevin; Taroni, Franco; Boylan, Kevin B; Van Blitterswijk, Marka; Rademakers, Rosa; Esteban-Pérez, Jesús; García-Redondo, Alberto; Van Damme, Phillip; Robberecht, Wim; Chio, Adriano; Gellera, Cinzia; Drepper, Carsten; Sendtner, Michael; Ratti, Antonia; Glass, Jonathan D; Mora, Jesús S; Basak, Nazli A; Hardiman, Orla; Ludolph, Albert C; Andersen, Peter M; Weishaupt, Jochen H; Brown, Robert H; Al-Chalabi, Ammar; Silani, Vincenzo; Shaw, Christopher E; van den Berg, Leonard H; Veldink, Jan H; Landers, John E

    2016-01-01

    To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a

  14. Insulin-like growth factor system in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Wilczak, N; de Keyser, J; Cianfarani, S; Clemmons, DR; Savage, MO

    2005-01-01

    Insulin-like growth factor-I (IGF-I) is a neurotrophic factor with insulin-like metabolic activities, and possesses potential clinical applications, particularly in neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is a chronic progressive devastating disorder of the central nervous

  15. Mortality from amyotrophic lateral sclerosis in Finland, 1986-1995

    DEFF Research Database (Denmark)

    Maasilta, P.; Jokelainen, M.; Löytönen, M.

    2001-01-01

    Objective - To study the possible changes, between 1986 and 1995, in the mortality due to amyotrophic lateral sclerosis (ALS) among Finnish patients. Materials and methods - A total of 1000 deaths from ALS were extracted from the Finnish Death Certificate Register for the study years. General...

  16. Amyotrophic lateral sclerosis: clinical features and current treatment approaches

    Directory of Open Access Journals (Sweden)

    Tuba Tulay Koca

    2015-06-01

    Full Text Available Amyotrophic lateral sclerosis also known as Lou Gehring's disease, is the most common motor neuron disease characterized by motor neuron degeneration in the primary cortex, brainstem and spinal cord. This leads to widespread paralysis, respiratory insufficiency and death within an average of 3-5 years from disease onset. Majority of cases is sporadic and only 10% have a family story. One of the most interesting discovery in the field of neurodegeneration in recent years is genetic mutation in the C9orf72 (chromosome 9 open reading frame 72 gene, the most common mutation found to be causative of frontotemporal dementia, amyotrophic lateral sclerosis and concomitant of these two diseases. Currently curative therapy for amyotrophic lateral sclerosis is lacking. To date, one medication, Riluzole, has been proved to prolong survival, approximately 3-5 months, in amyotrophic lateral sclerosis. Researches aim to slow disease progression by targeting known pathophysiological pathways or genetics defects. Only symptomatic care to improve quality of life and survival is suggested. These includes respiratory and nutrition support; dysphagia and gastrostomy management; communication and mobility programs; spasticity prevention; pain medication; management of cognitive dysfunction, depression, mood dysorders (especially apathy, fatigue, sleep disturbance and prevention of deep venous thrombosis. [Archives Medical Review Journal 2015; 24(2.000: 182-194

  17. Caregiver burden in amyotrophic lateral sclerosis: A systematic review

    NARCIS (Netherlands)

    de Wit, Jessica; Bakker, Leonhard A.; van Groenestijn, Annerieke C.; van den Berg, Leonard H.; Schröder, Carin D.; Visser-Meily, Johanna Ma; Beelen, Anita

    2018-01-01

    Background: Informal caregivers of patients with amyotrophic lateral sclerosis experience increased levels of caregiver burden as the disease progresses. Insight in the factors related to caregiver burden is needed in order to develop supportive interventions. Aim: To evaluate the evidence on

  18. Prior medical conditions and the risk of amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Seelen, Meinie; van Doormaal, Perry T. C.; Visser, Anne E.; Huisman, Mark H. B.; Roozekrans, Margot H. J.; de Jong, Sonja W.; van der Kooi, Anneke J.; de Visser, Marianne; Voermans, Nicol C.; Veldink, Jan H.; van den Berg, Leonard H.

    2014-01-01

    Sporadic amyotrophic lateral sclerosis (ALS) is believed to be a complex disease in which multiple exogenous and genetic factors interact to cause motor neuron degeneration. Elucidating the association between medical conditions prior to the first symptoms of ALS could lend support to the theory

  19. Structural MRI reveals cortical thinning in amyotrophic lateral sclerosis.

    NARCIS (Netherlands)

    Verstraete, E.; Veldink, J.H.; Hendrikse, J.; Schelhaas, H.J.; Heuvel, M.P. van den; Berg, L.H. van den

    2012-01-01

    OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal disease characterised by combined upper and lower motor neuron degeneration. An early and accurate diagnosis is important for patient care and might facilitate the search for a more effective therapy. MRI was used to study the whole cortical

  20. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

    NARCIS (Netherlands)

    McLaughlin, Russell L.; Schijven, Dick; van Rheenen, Wouter; van Eijk, Kristel R.; O'Brien, Margaret; Kahn, René S.; Ophoff, Roel A.; Goris, An; Bradley, Daniel G.; Al-Chalabi, Ammar; van den Berg, Leonard H.; Luykx, Jurjen J.; Hardiman, Orla; Veldink, Jan H.; Shatunov, Aleksey; Dekker, Annelot M.; Diekstra, Frank P.; Pulit, Sara L.; van der Spek, Rick A. A.; van Doormaal, Perry T. C.; Sproviero, William; Jones, Ashley R.; Nicholson, Garth A.; Rowe, Dominic B.; Pamphlett, Roger; Kiernan, Matthew C.; Bauer, Denis; Kahlke, Tim; Williams, Kelly; Eftimov, Filip; Fogh, Isabella; Ticozzi, Nicola; Lin, Kuang; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E.; Shaw, Pamela J.; Hardy, John; Orrell, Richard W.; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Petri, Susanne; Abdulla, Susanna; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; van Deerlin, Vivianna M.; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Basak, Nazli; Meitinger, Thomas; Lichtner, Peter; Blagojevic-Radivojkov, Milena; Andres, Christian R.; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A. M.; Saker-Delye, Safa; Dürr, Alexandra; Wood, Nicholas; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöuthen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G.; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; van der Kooi, Anneke J.; de Visser, Marianne; Weber, Markus; Shaw, Christopher E.; Smith, Bradley N.; Pansarasa, Orietta; Cereda, Cristina; del Bo, Roberto; Comi, Giacomo P.; D'alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simon; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Blair, Ian; Leigh, P. Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C.; Weishaupt, Jochen H.; Robberecht, Wim; van Damme, Philip; Brown, Robert H.; Glass, Jonathan; Landers, John E.; Andersen, Peter M.; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; van Es, Michael A.; Pasterkamp, R. Jeroen; Lewis, Cathryn M.; Breen, Gerome; Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberley D.; Chan, Raymond C. K.; Chan, Ronald Y. L.; Chen, Eric Y. H.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; del Favero, Jurgen; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julià, Antonio; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kähler, Anna K.; Laurent, Claudine; Lee, Jimmy; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lönnqvist, Jouko; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Müller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C. A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Söderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H. R.; Bramon, Elvira; Buxbaum, Joseph D.; Børglum, Anders D.; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tõnu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jönsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; St Clair, David; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Sullivan, Patrick F.; O'Donovan, Michael C.

    2017-01-01

    We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide

  1. Evidence for an oligogenic basis of amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van Blitterswijk, Marka; van Es, Michael A.; Hennekam, Eric A. M.; Dooijes, Dennis; van Rheenen, Wouter; Medic, Jelena; Bourque, Pierre R.; Schelhaas, Helenius J.; van der Kooi, Anneke J.; de Visser, Marianne; de Bakker, Paul I. W.; Veldink, Jan H.; van den Berg, Leonard H.

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a substantial heritable component. In pedigrees affected by its familial form, incomplete penetrance is often observed. We hypothesized that this could be caused by a complex inheritance of risk variants in multiple

  2. Amyotrophic lateral sclerosis: risk factors in the genome and exposome

    NARCIS (Netherlands)

    van Doormaal, P.T.C.

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease resulting in progressive weakness and death in three to five years on average. In most patients there are no family members with ALS, and therefore an interplay of genetic and environmental risk factors is thought to be

  3. Cultivating stem cells for treating amyotrophic lateral sclerosis

    Science.gov (United States)

    Li, Shengwen Calvin; Yin, Hong Zhen; Loudon, William G; Weiss, John H

    2012-01-01

    This editorial addresses the current challenges and future directions in the use of stem cells as an approach for treating amyotrophic lateral sclerosis. A wide variety of literature has been reviewed to enlighten the reader on the many facets of stem cell research that are important to consider before using them for a cell based therapy. PMID:23516096

  4. Amyotrophic lateral sclerosis: genetic susceptibility factors and pleiotropy

    NARCIS (Netherlands)

    Diekstra, F.P.

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness, spasticity, dysarthria and, ultimately, respiratory muscle insufficiency. These symptoms are caused by the loss of motor neurons in both the brain and in the anterior horn of the

  5. Spatiotemporal Coupling of the Tongue in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Kuruvilla, Mili S.; Green, Jordan R.; Yunusova, Yana; Hanford, Kathy

    2012-01-01

    Purpose: The primary aim of the investigation was to identify deficits in spatiotemporal coupling between tongue regions in amyotrophic lateral sclerosis (ALS). The relations between disease-related changes in tongue movement patterns and speech intelligibility were also determined. Methods: The authors recorded word productions from 11…

  6. Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Pryce, Gareth; Baker, David

    2015-01-01

    There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

  7. Temporal lobe pathology in amyotrophic lateral sclerosis. Do amyotrophic lateral sclerosis and Alzheimer's disease share a common etiological factor?

    NARCIS (Netherlands)

    Smitt, P. A.; Troost, D.; Louwerse, E. S.; de Jong, J. M.; van Kessel, D. T.; de Leeuw, M. A.

    1993-01-01

    An autopsy study was performed on temporal lobe samples from 20 non-demented patients with amyotrophic lateral sclerosis (ALS), 17 age-matched non-demented controls and 4 Alzheimer's disease (AD) patients. Formalin fixed, paraffin embedded sections from the hippocampus with adjacent parahippocampal

  8. The genetic basis of amyotrophic lateral sclerosis: recent breakthroughs

    Directory of Open Access Journals (Sweden)

    Eykens C

    2015-10-01

    Full Text Available Caroline Eykens,1,2 Wim Robberecht1–31Research Group Experimental Neurology, Department of Neurosciences, KU Leuven – University of Leuven, Leuven, Belgium; 2Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium; 3Department of Neurology, University Hospitals Leuven, Leuven, BelgiumAbstract: Deciphering the genetic architecture of amyotrophic lateral sclerosis (ALS, an adult-onset neurodegenerative disorder of the motor neuron system, is important to understand the etiology of this fatal disease as well as to develop customized ALS therapies based on the patient's genetic fingerprint. In this review, we discuss the genetic basis of ALS, and attempt to link the causal genes to three highly interrelated pathogenic mechanisms: dysproteostasis, RNA dysregulation, and axon dysfunction. In addition, we address the clinical and biological implications of these genetic findings. Furthermore, we explore to what extent genetic knowledge can be converted into targeted and personalized treatments.Keywords: amyotrophic lateral sclerosis, frontotemporal dementia, genetics, disease modifiers, personalized medicine

  9. Frontal assessment battery and frontal atrophy in amyotrophic lateral sclerosis

    OpenAIRE

    Terada, Tatsuhiro; Miyata, Jun; Obi, Tomokazu; Kubota, Manabu; Yoshizumi, Miho; Yamazaki, Kinya; Mizoguchi, Kouichi; Murai, Toshiya

    2017-01-01

    Abstract Objectives To determine the potential utility of the frontal assessment battery (FAB) in assessing cognitive impairments in amyotrophic lateral sclerosis (ALS), we investigated the association between the FAB score and regional gray matter volume, and ascertained whether the regional brain alterations related to cognitive impairments occur in relatively mild stage of ALS. Materials and Methods Twenty?four ALS patients with a Mini?Mental State Examination score of >23, a normal score ...

  10. Metal-deficient SOD1 in amyotrophic lateral sclerosis

    OpenAIRE

    Hilton, James B.; White, Anthony R.; Crouch, Peter J.

    2015-01-01

    Mutations to the ubiquitous antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) were the first established genetic cause of the fatal, adult-onset neurodegenerative disease amyotrophic lateral sclerosis (ALS). It is widely accepted that these mutations do not cause ALS via a loss of antioxidant function, but elucidating the alternate toxic gain of function has proven to be elusive. Under physiological conditions, SOD1 binds one copper ion and one zinc ion per monomer to form a highly stable ...

  11. Neuroimaging of multimodal sensory stimulation in Amyotrophic Lateral Sclerosis (ALS)

    OpenAIRE

    Lulé , Dorothée; Diekmann , Volker; Müller , Hans-Peter; Kassubek , Jan; Ludolph , Albert C; Birbaumer , Niels

    2010-01-01

    Abstract Aim: Structural and functional imaging techniques were combined to investigate sensory system function in amyotrophic lateral sclerosis (ALS). Methods: Functional magnetic resonance imaging (fMRI) was used to investigate cortical activity during visual, auditory, and somato-sensory stimulation in fourteen ALS patients and eighteen control subjects. Changes in amplitude, latency and duration of the BOLD response were modelled. Furthermore, diffusion tensor imaging was ...

  12. Amyotrophic lateral sclerosis – a motor neuron disease. Case report

    Directory of Open Access Journals (Sweden)

    Maja Rubinowicz-Zasada

    2015-03-01

    Full Text Available Amyotrophic lateral sclerosis, also known as Charcot’s disease and motor neuron disease, is a progressive neurodegenerative disease that causes muscle weakness, paralysis, and ultimately, respiratory failure. The aetiology and the pathogenesis of the syndrome remain unknown. Most people live 2–5 years after their first signs of the disease. There is no cure or effective treatment. We present a case of a female patient affected by progressing Charcot’s disease. On the Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R, the patient obtained 21 points. Atrophy and muscle spasm were very extended. Electromyography revealed features of coexisting denervation and reinnervation in the examined muscles. A growing number of Charcot’s disease cases require multidirectional actions to meet patient’s physical, emotional, and nutritional needs. Amyotrophic lateral sclerosis is an incurable disease. However, it is possible to relieve its symptoms by applying systematic physical rehabilitation.

  13. 38 CFR 3.318 - Presumptive service connection for amyotrophic lateral sclerosis.

    Science.gov (United States)

    2010-07-01

    ... connection for amyotrophic lateral sclerosis. 3.318 Section 3.318 Pensions, Bonuses, and Veterans' Relief... sclerosis. (a) Except as provided in paragraph (b) of this section, the development of amyotrophic lateral sclerosis manifested at any time after discharge or release from active military, naval, or air service is...

  14. Palliative care in amyotrophic lateral sclerosis: a review of current international guidelines and initiatives.

    LENUS (Irish Health Repository)

    Bede, Peter

    2011-04-01

    Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition. Optimal management requires a palliative approach from diagnosis with emphasis on patient autonomy, dignity and quality of life.

  15. Predicting functional decline and survival in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Ong, Mei-Lyn; Tan, Pei Fang; Holbrook, Joanna D

    2017-01-01

    Better predictors of amyotrophic lateral sclerosis disease course could enable smaller and more targeted clinical trials. Partially to address this aim, the Prize for Life foundation collected de-identified records from amyotrophic lateral sclerosis sufferers who participated in clinical trials of investigational drugs and made them available to researchers in the PRO-ACT database. In this study, time series data from PRO-ACT subjects were fitted to exponential models. Binary classes for decline in the total score of amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) (fast/slow progression) and survival (high/low death risk) were derived. Data was segregated into training and test sets via cross validation. Learning algorithms were applied to the demographic, clinical and laboratory parameters in the training set to predict ALSFRS-R decline and the derived fast/slow progression and high/low death risk categories. The performance of predictive models was assessed by cross-validation in the test set using Receiver Operator Curves and root mean squared errors. A model created using a boosting algorithm containing the decline in four parameters (weight, alkaline phosphatase, albumin and creatine kinase) post baseline, was able to predict functional decline class (fast or slow) with fair accuracy (AUC = 0.82). However similar approaches to build a predictive model for decline class by baseline subject characteristics were not successful. In contrast, baseline values of total bilirubin, gamma glutamyltransferase, urine specific gravity and ALSFRS-R item score-climbing stairs were sufficient to predict survival class. Using combinations of small numbers of variables it was possible to predict classes of functional decline and survival across the 1-2 year timeframe available in PRO-ACT. These findings may have utility for design of future ALS clinical trials.

  16. Predicting functional decline and survival in amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Mei-Lyn Ong

    Full Text Available Better predictors of amyotrophic lateral sclerosis disease course could enable smaller and more targeted clinical trials. Partially to address this aim, the Prize for Life foundation collected de-identified records from amyotrophic lateral sclerosis sufferers who participated in clinical trials of investigational drugs and made them available to researchers in the PRO-ACT database.In this study, time series data from PRO-ACT subjects were fitted to exponential models. Binary classes for decline in the total score of amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R (fast/slow progression and survival (high/low death risk were derived. Data was segregated into training and test sets via cross validation. Learning algorithms were applied to the demographic, clinical and laboratory parameters in the training set to predict ALSFRS-R decline and the derived fast/slow progression and high/low death risk categories. The performance of predictive models was assessed by cross-validation in the test set using Receiver Operator Curves and root mean squared errors.A model created using a boosting algorithm containing the decline in four parameters (weight, alkaline phosphatase, albumin and creatine kinase post baseline, was able to predict functional decline class (fast or slow with fair accuracy (AUC = 0.82. However similar approaches to build a predictive model for decline class by baseline subject characteristics were not successful. In contrast, baseline values of total bilirubin, gamma glutamyltransferase, urine specific gravity and ALSFRS-R item score-climbing stairs were sufficient to predict survival class.Using combinations of small numbers of variables it was possible to predict classes of functional decline and survival across the 1-2 year timeframe available in PRO-ACT. These findings may have utility for design of future ALS clinical trials.

  17. Muscle ultrasound imaging in the diagnosis of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Yu. N. Rushkevich

    2014-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is the most common form of motor neuron disease. This pathology is characterized by the involvement of central and peripheral motor neurons in the pathological process. One  f the specific symptoms of ALS is fasciculations - involuntary muscle contractions that may occasionally precede the development of muscle weakness and atrophies. This paper summarizes the accumulated practical experience in using muscle ultrasound study in the diagnosis of fasciculations and their prevalence as an early sign of anterior corneal lesion in ALS.

  18. Apo-Ferritin as a Therapeutic Treatment for Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    2013-09-01

    treatment of spastic muscular disease. Although still in its infancy, our study has presented an exciting, unexplored– but easily clinically implemented... Treatment for Amyotrophic Lateral Sclerosis PRINCIPAL INVESTIGATOR: James R. Connor, Ph.D CONTRACTING ORGANIZATION: Pennsylvania...DATES COVERED 1 September 2011 – 31 August 2013 4. TITLE AND SUBTITLE Apo-Ferritin as a Therapeutic Treatment for Amyotrophic Lateral Sclerosis

  19. Amyotrophic lateral sclerosis multiprotein biomarkers in peripheral blood mononuclear cells.

    Directory of Open Access Journals (Sweden)

    Giovanni Nardo

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC, a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%, and from patients with neurological disorders that may resemble ALS (91%, between two levels of disease severity (90%, and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms.

  20. Amyotrophic lateral sclerosis: applications of stem cells – an update

    Directory of Open Access Journals (Sweden)

    Lidia Cova

    2010-10-01

    Full Text Available Lidia Cova1, Vincenzo Silani21Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy; 2Department of Neurology and Laboratory of Neuroscience, “Dino Ferrari” Center, Università degli Studi di Milano, IRCCS Istituto Auxologico Italiano, Milano, ItalyAbstract: Neurodegenerative diseases are a growing public health challenge, and amyotrophic lateral sclerosis (ALS remains a fatal incurable disease. The advent of stem cell therapy has opened new horizons for both researchers and ALS patients, desperately looking for a treatment. ALS must be considered a systemic disease affecting many cell phenotypes besides motor neurons, even outside the central nervous system. Cell replacement therapy needs to address the specific neurobiological issues of ALS to safely and efficiently reach clinical settings. Moreover, the enormous potential of induced pluripotent cells directly derived from patients for modeling and understanding the pathological mechanisms, in correlation with the discoveries of new genes and animal models, provides new opportunities that need to be integrated with previously described transplantation strategies. Finally, a careful evaluation of preclinical data in conjunction with wary patient choice in clinical trials needs to be established in order to generate meaningful results.Keywords: amyotrophic lateral sclerosis, regenerative medicine, stem cell therapy, clinical trials

  1. Case-control study of amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Deapen, D.M.; Henderson, B.E.

    1986-05-01

    The authors conducted a study of 518 amyotrophic lateral sclerosis patients identified between 1977 and 1979 and 518 controls to investigate putative risk factors for this disease. Occupations at risk of electrical exposure were reported more often by patients (odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.4-13.0) as were electrical shocks producing unconsciousness (OR = 2.8, 95% CI = 1.0-9.9). Although an overall excess of physical trauma associated with unconsciousness was observed in the amyotrophic lateral sclerosis patients (OR = 1.6, 95% CI = 1.0-2.4), the effect was inversely associated with duration of the unconscious episodes, suggesting an effect of recall bias. Only slight differences were found for surgical traumata to the nervous system. Parkinsonism was reported more often among first degree relatives of cases (OR = 2.7, 95% CI = 1.1-7.6). The frequencies of prior poliomyelitis or other central nervous system diseases were similar for patients and controls. Occupational exposure to selected toxic substances was similar for patients and controls except for the manufacture of plastics (OR = 3.7, 95% CI = 1.0-20.5), although few details of these exposures were provided. No differences in occupations with exposure to animal skins or hides were observed.

  2. [Multidisciplinary Management and Neurorehabilitation of Patients with Amyotrophic Lateral Sclerosis].

    Science.gov (United States)

    Budinčević, H; Marčinko Budinčević, A; Kos, M; Vlašić, S; Bartolović, J; Benko, S; Ostojić, V; Soldo Butković, S

    2016-04-01

    Patients with amyotrophic lateral sclerosis require comprehensive care with a multidisciplinary approach, which is individually adjusted to each patient. The goals of neurorehabilitation should be adjusted to the stage of disease. In early stages, physical therapy is focused on preserving and optimizing motor and respiratory function. At this stage, family should be involved to partake in desired activities and be informed regarding the natural course of the disease. In late stages, physical therapy is focused on preventing respiratory complications and contractures, and orthotics may also be recommended. The onset of dysarthria should trigger swallowing and pulmonary function testing. Swallowing maneuvers should be tried at the onset of symptoms, later feeding tubes or percutaneous gastrostomy tube is necessary. Noninvasive mechanical ventilation may delay the need of tracheostomy and invasive mechanical ventilation. The key objectives of multidisciplinary teams are to optimize medical care, facilitate communication, and thus to improve the quality of care and quality of life.

  3. Neurologic disorders: amyotrophic lateral sclerosis, myasthenia gravis, multiple sclerosis, and poliomyelitis.

    Science.gov (United States)

    Garfinkle, T J; Kimmelman, C P

    1982-01-01

    The patient who has multiple cranial neuropathies may pose a diagnostic dilemma. The neurologic disorders of amyotrophic lateral sclerosis, multiple sclerosis, myasthenia gravis, and poliomyelitis often cause bulbar dysfunctions such as diplopia, facial weakness, slurred or hypernasal speech, dysphagia, and hoarseness. In general, treatment is supportive and is directed toward restoring or aiding lost function (i.e., tracheostomy, esophagostomy, and cricopharyngeal myotomy). The relative infrequency of these disorders can lead to delays in diagnosis and rehabilitative therapy.

  4. Progress in clinical diagnosis of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    YANG Qiong

    2012-06-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease, mainly involving the pyramidal tract, brain stem and spinal cord anterior horn cells, manifests as progressive muscle atrophy, weakness and cramps, as well as cognitive impairment, and may overlap with frontotemporal dementia. ALS is familial in 5% of cases, whose clinical manifestations are similar to sporadic. The diagnosis is made mainly based on clinical manifestations, using internationally recognized consensus standard, after rule out conditions that can mimic ALS. Genetic testing provides a new way to accelerate the diagnostic process for early intervention. Part of the gene mutations are associated with specific phenotypes. According to this, prognosis assessment and genetic counseling are able to carry out.

  5. Natural history of muscle cramps in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Caress, James B; Ciarlone, Stephanie L; Sullivan, Elizabeth A; Griffin, Leah P; Cartwright, Michael S

    2016-04-01

    Muscle cramping is a common symptom in amyotrophic lateral sclerosis (ALS) that lacks efficacious treatment. The natural history of this symptom is unknown, which hampers efforts to design optimal clinical trials. We surveyed early stage ALS patients about their experience with cramps each month by phone for up to 21 months. Cramps developed in 95% of patients over the course of their disease. The number of cramps experienced by an individual varied widely from month-to-month and trended lower after the first year of illness (P = 0.26). Those with limb-onset and age >60 years had more cramps than bulbar-onset (P cramps experienced suggests that clinical trials will need to use crossover designs or large numbers of participants, even when the treatment effect is substantial. © 2015 Wiley Periodicals, Inc.

  6. The Natural History of Muscle Cramps in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Caress, James B.; Ciarlone, Stephanie L.; Sullivan, Elizabeth A.; Griffin, Leah P.; Cartwright, Michael S.

    2015-01-01

    Introduction Muscle cramping is a common symptom in amyotrophic lateral sclerosis (ALS) without efficacious treatment. The natural history of this symptom is unknown, which hampers efforts to design optimal clinical trials. Methods We surveyed early stage ALS patients about their experience with cramps each month by phone for up to 21 months. Results Cramps developed in 95% of patients over the course of their disease. The number of cramps experienced by an individual varied widely from month-to-month and trended lower after the first year of illness (P = 0.26). Those with limb-onset and age >60 years had more cramps than bulbar-onset (Pcramps experienced suggests that clinical trials will need to use crossover designs or large numbers of participants, even when the treatment effect is substantial. PMID:26332705

  7. Hypoparathyroidism: A rare mimic of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Hakeem, Haris; Uz Zaman, Masood; Khan, Sara

    2017-03-01

    Amyotrophic lateral sclerosis (ALS) carries a grim prognosis. Various ALS mimics have been reported and should be excluded before confirming this diagnosis. We report the case of a 61-year-old man who presented with progressively worsening limb weakness and dysphagia. His examination showed mixed upper and lower motor neuron signs without sensory impairment. ALS was suspected, however, atypical diffuse pain prompted diagnostic work-up to exclude other causes. Electrodiagnostic testing was suggestive of a sensorimotor polyneuropathy with superimposed diffuse active denervation suspicious for anterior horn cell degeneration. Brain MRI showed bilateral basal ganglia and thalamic calcifications. Laboratory studies confirmed the diagnosis of hypoparathyroidism. Treatment with calcium and vitamin D resulted in significant improvement at 6 months follow-up. Hypoparathyroidism, a treatable endocrinopathy, can rarely present clinically as ALS. In atypical cases, this should be ruled out before making a final diagnosis. Muscle Nerve, 2016 Muscle Nerve 55: 437-439, 2017. © 2016 Wiley Periodicals, Inc.

  8. Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?

    Directory of Open Access Journals (Sweden)

    Pamela J. Shaw

    2017-05-01

    Full Text Available Protein homeostasis (proteostasis, the correct balance between production and degradation of proteins, is essential for the health and survival of cells. Proteostasis requires an intricate network of protein quality control pathways (the proteostasis network that work to prevent protein aggregation and maintain proteome health throughout the lifespan of the cell. Collapse of proteostasis has been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS, the most common adult onset motor neuron disorder. Here, we review the evidence linking dysfunctional proteostasis to the etiology of ALS and discuss how ALS-associated insults affect the proteostasis network. Finally, we discuss the potential therapeutic benefit of proteostasis network modulation in ALS.

  9. RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Stéphane Mathis

    2018-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

  10. Alternative Fuels in Epilepsy and Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Tefera, Tesfaye W; Tan, Kah Ni; McDonald, Tanya S; Borges, Karin

    2017-06-01

    This review summarises the recent findings on metabolic treatments for epilepsy and Amyotrophic Lateral Sclerosis (ALS) in honour of Professor Ursula Sonnewald. The metabolic impairments in rodent models of these disorders as well as affected patients are being discussed. In both epilepsy and ALS, there are defects in glucose uptake and reduced tricarboxylic acid (TCA) cycling, at least in part due to reduced amounts of C4 TCA cycle intermediates. In addition there are impairments in glycolysis in ALS. A reduction in glucose uptake can be addressed by providing the brain with alternative fuels, such as ketones or medium-chain triglycerides. As anaplerotic fuels, such as the triglyceride of heptanoate, triheptanoin, refill the TCA cycle C4/C5 intermediate pool that is deficient, they are ideal to boost TCA cycling and thus the oxidative metabolism of all fuels.

  11. Oral appliance to assist non-invasive ventilation in a patient with amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Veldhuis, Steffanie K. B.; Doff, Michiel H. J.; Stegenga, Boudewijn; Nieuwenhuis, Jellie A.; Wijkstra, Peter J.

    From the moment the respiratory muscle groups are affected in amyotrophic lateral sclerosis (ALS), respiratory complications will be the major cause of morbidity and mortality. Untreated respiratory muscle impairment leads to respiratory insufficiency and additionally to difficulties in airway

  12. Preservation of the nucleus X-pelvic floor motosystem in amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Schrøder, H D; Reske-Nielsen, E

    1984-01-01

    Fourteen cases of amyotrophic lateral sclerosis (ALS) were investigated neuropathologically, emphazising the sacral spinal cord which contains Onuf's nucleus X. The nucleus innervates the pelvic sphincters. In two cases, small striated pelvic muscles were studied. No changes characteristic of ALS...

  13. MONITORING DISEASE PROGRESSION USING HIGH-DENSITY MOTOR UNIT NUMBER ESTIMATION IN AMYOTROPHIC LATERAL SCLEROSIS

    NARCIS (Netherlands)

    van Dijk, Johannes P.; Schelhaas, Helenius J.; van Schaik, Ivo N.; Janssen, Henny M. H. A.; Stegeman, Dick F.; Zwarts, Machiel J.

    2010-01-01

    In amyotrophic lateral sclerosis (ALS), progressive motor neuron loss causes severe weakness. Functional measurements tend to underestimate the underlying pathology because of collateral reinnervation. A more direct marker of lower motor neuron loss is of significant importance. We evaluated

  14. Brain perfusion imaging in amyotrophic lateral sclerosis with dementia

    International Nuclear Information System (INIS)

    Ishikawa, Takehisa; Morita, Mitsuya; Nakano, Imaharu

    2007-01-01

    Single photon emission computed tomography (SPECT) studies have been applied for evaluation of regional cerebral blood flow (rCBF) in various neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and ALS with dementia (ALS-D). Brain perfusion SPECT using statistical image analysis is useful for accurate and objective diagnosis to evaluate slight decreases in rCBF, even in cases difficult to assess by visual inspection. We have used statistical parametric mapping (SPM), three-dimensional stereotactic surface projection (3D-SSP), easy Z-score imaging system (eZIS) as statistical image analyses. ALS-D cases, even if a case manifests minimal mentality change, showed obvious rCBF reduction in the bilateral prefrontal area with some irregularity and laterality of its decrease. This abnormality was clear in ALS-D compared with classic ALS. Our study has demonstrated that brain perfusion SPECT imaging using statistical image analyses is quite useful as an adjunct to presume the existence of dementia in ALS, even if ALS patients have trouble in verbal or manual communication of the language because of progressive bulbar symptoms and muscle weakness. Thus, for ALS patients with any subtle signs and symptoms suggesting dementia, we recommend a SPECT study with use of statistical image analyses. (author)

  15. Frontotemporal Dysfunction in Amyotrophic Lateral Sclerosis: A Discriminant Function Analysis.

    Science.gov (United States)

    Nidos, Andreas; Kasselimis, Dimitrios S; Simos, Panagiotis G; Rentzos, Michael; Alexakis, Theodoros; Zalonis, Ioannis; Zouvelou, Vassiliki; Potagas, Constantin; Evdokimidis, Ioannis; Woolley, Susan C

    2016-01-01

    There is growing evidence for extramotor dysfunction (EMd) in amyotrophic lateral sclerosis (ALS), with a reported prevalence of up to 52%. In the present study, we explore the clinical utility of a brief neuropsychological battery for the investigation of cognitive, behavioral, and language deficits in patients with ALS. Thirty-four consecutive ALS patients aged 44-89 years were tested with a brief neuropsychological battery, including executive, behavioral, and language measures. Patients were initially classified as EMd or non-EMd based on their scores on the frontal assessment battery (FAB). Between-group comparisons revealed significant differences in all measures (p < 0.01). Discriminant analysis resulted in a single canonical function, with all tests serving as significant predictors. This function agreed with the FAB in 13 of 17 patients screened as EMd and identified extramotor deficits in 2 additional patients. Overall sensitivity and specificity estimates against FAB were 88.2%. We stress the importance of discriminant function analysis in clinical neuropsychological assessment and argue that the proposed neuropsychological battery may be of clinical value, especially when the option of extensive and comprehensive neuropsychological testing is limited. The psychometric validity of an ALS-frontotemporal dementia diagnosis using neuropsychological tests is also discussed. © 2015 S. Karger AG, Basel.

  16. Communication and pragmatic breakdowns in amyotrophic lateral sclerosis patients.

    Science.gov (United States)

    Bambini, Valentina; Arcara, Giorgio; Martinelli, Ilaria; Bernini, Sara; Alvisi, Elena; Moro, Andrea; Cappa, Stefano F; Ceroni, Mauro

    2016-02-01

    While there is increasing attention toward cognitive changes in amyotrophic lateral sclerosis (ALS), the domain of pragmatics, defined as the ability to integrate language and context to engage in successful communication, remains unexplored. Here we tested pragmatic abilities in 33 non-demented ALS patients and 33 healthy controls matched for age and education through 6 different tasks, ranging from discourse organization to the comprehension of figurative language, further grouped in three composite measures for pragmatic production, pragmatic comprehension and global pragmatic abilities. For a subgroup of patients, assessment included executive functions and social cognition skills. ALS patients were impaired on all pragmatic tasks relative to controls, with 45% of the patients performing below cut-off in at least one pragmatic task, and 36% impaired on the global pragmatic score. Pragmatic breakdowns were more common than executive deficit as defined by the consensus criteria, and approximately as prevalent as deficits in social cognition. Multiple regression analyses support the idea of an interplay of executive and social cognition abilities in determining the pragmatic performance, although all these domains show some degree of independence. These findings shed light on pragmatic impairment as a relevant dimension of ALS, which deserves further consideration in defining the cognitive profile of the disease, given its vital role for communication and social interaction in daily life. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Manfredi, Giovanni; Kawamata, Hibiki

    2016-06-01

    Physical and functional interactions between mitochondria and the endoplasmic reticulum (ER) are crucial for cell life. These two organelles are intimately connected and collaborate to essential processes, such as calcium homeostasis and phospholipid biosynthesis. The connections between mitochondria and endoplasmic reticulum occur through structures named mitochondria associated membranes (MAMs), which contain lipid rafts and a large number of proteins, many of which serve multiple functions at different cellular sites. Growing evidence strongly suggests that alterations of ER-mitochondria interactions are involved in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a devastating and rapidly fatal motor neuron disease. Mutations in proteins that participate in ER-mitochondria interactions and MAM functions are increasingly being associated with genetic forms of ALS and other neurodegenerative diseases. This evidence strongly suggests that, rather than considering the two organelles separately, a better understanding of the disease process can derive from studying the alterations in their crosstalk. In this review we discuss normal and pathological ER-mitochondria interactions and the evidence that link them to ALS. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Dynamic markers of altered gait rhythm in amyotrophic lateral sclerosis

    Science.gov (United States)

    Hausdorff, J. M.; Lertratanakul, A.; Cudkowicz, M. E.; Peterson, A. L.; Kaliton, D.; Goldberger, A. L.

    2000-01-01

    Amyotrophic lateral sclerosis (ALS) is a disorder marked by loss of motoneurons. We hypothesized that subjects with ALS would have an altered gait rhythm, with an increase in both the magnitude of the stride-to-stride fluctuations and perturbations in the fluctuation dynamics. To test for this locomotor instability, we quantitatively compared the gait rhythm of subjects with ALS with that of normal controls and with that of subjects with Parkinson's disease (PD) and Huntington's disease (HD), pathologies of the basal ganglia. Subjects walked for 5 min at their usual pace wearing an ankle-worn recorder that enabled determination of the duration of each stride and of stride-to-stride fluctuations. We found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls. In addition, advanced ALS, HD, and PD were associated with certain common, as well as apparently distinct, features of altered stride dynamics. Thus stride-to-stride control of gait rhythm is apparently compromised with ALS. Moreover, a matrix of markers based on gait dynamics may be useful in characterizing certain pathologies of motor control and, possibly, in quantitatively monitoring disease progression and evaluating therapeutic interventions.

  19. GNE missense mutation in recessive familial amyotrophic lateral sclerosis.

    Science.gov (United States)

    Köroğlu, Çiğdem; Yılmaz, Rezzak; Sorgun, Mine Hayriye; Solakoğlu, Seyhun; Şener, Özden

    2017-12-01

    Amyotrophic lateral sclerosis (ALS) is a motor neuron disease eventually leading to death from respiratory failure. Recessive inheritance is very rare. Here, we describe the clinical findings in a consanguineous family with five men afflicted with recessive ALS and the identification of the homozygous mutation responsible for the disorder. The onset of the disease ranged from 12 to 35 years of age, with variable disease progressions. We performed clinical investigations including metabolic and paraneoplastic screening, cranial and cervical imaging, and electrophysiology. We mapped the disease gene to 9p21.1-p12 with a LOD score of 5.2 via linkage mapping using genotype data for single-nucleotide polymorphism markers and performed exome sequence analysis to identify the disease-causing gene variant. We also Sanger sequenced all coding sequences of SIGMAR1, a gene reported as responsible for juvenile ALS in a family. We did not find any mutation in SIGMAR1. Instead, we identified a novel homozygous missense mutation p.(His705Arg) in GNE which was predicted as damaging by online tools. GNE has been associated with inclusion body myopathy and is expressed in many tissues. We propose that the GNE mutation underlies the pathology in the family.

  20. Writing Errors and Anosognosia in Amyotrophic Lateral Sclerosis with Dementia

    Directory of Open Access Journals (Sweden)

    Hiroo Ichikawa

    2008-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS with dementia (ALS-D is known to exhibit characteristics of frontotemporal dementia. However, in clinical situations, it is often difficult to evaluate their cognitive functions because of impaired voluntary speech and physical disabilities. In order to identify characteristic and diagnostic cognitive symptoms of relatively advanced ALS-D patients, we retrospectively reviewed the clinical features of seven cases of clinically definitive ALS who had dementia, impaired voluntary speech, and physical disability. Their medical records showed that six out of seven patients made writing errors, and all of the patients demonstrated anosognosia. The writing errors consisted of paragraphia such as substitution, omission, or syntactic errors with individual differences in error types. Dissociation between kana and kanji were also observed. Anosognosia was evaluated by a self-rating scale with which the patients and the medical staff evaluated the patient's physical ability; the results indicated a large discrepancy between the evaluation by the patients and the medical staff. We emphasize that aphasic writing errors have been underestimated, particularly in ALS-D patients with impaired voluntary speech. We also reported that anosognosia was the most important and quantifiable symptom in ALS-D. The relationship between writing errors and anosognosia should be investigated further.

  1. Ethical issues in invasive mechanical ventilation for amyotrophic lateral sclerosis.

    Science.gov (United States)

    Hirano, Yuko; Yamazaki, Yoshihiko

    2010-01-01

    Currently in Japan, discontinuing an invasive mechanical ventilator (IMV) is illegal; therefore IMV-related decision making is a crucial issue. This study examined IMV decision-making factors and psychological conflict in 50 patients with amyotrophic lateral sclerosis. The Herth Hope Index was used for the assessment of pre- and post-IMV conflict. Interviews identified some decision-making factors: patient's decision, patient's and family's mutual decision, family's decision, and emergency-induced without patient's or family's consent. Participants who experienced no IMV-related regret received sufficient prior IMV education from physicians and nurses, and time for reflection and family consultation. Their hope was similar to their pre-onset levels. Patients who received no prior IMV education accepted treatment as a natural progression. Their hope levels were lower than pre-onset. Those who received only a brief prior IMV explanation rejected the ventilator, experiencing regret if they were given an emergency IMV. Their hope levels were among the lowest. However, some of these patients managed to overcome their regret through being helped by nurses. Sufficient physician explanation and nursing advocacy for autonomous patient decision making are critical for improving hope in this patient group.

  2. Longitudinal diffusion tensor imaging in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Keil Carsten

    2012-11-01

    Full Text Available Abstract Background Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disorder, caused by progressive loss of motor neurons. Changes are widespread in the subcortical white matter in ALS. Diffusion tensor imaging (DTI detects pathological changes in white matter fibres in vivo, based on alterations in the degree (diffusivity, ADC and directedness (fractional anisotropy, FA of proton movement. Methods 24 patients with ALS and 24 age-matched controls received 1.5T DTI. FA and ADC were analyzed using statistical parametric mapping. In 15 of the 24 ALS patients, a second DTI was obtained after 6 months. Results Decreased FA in the corticospinal tract (CST and frontal areas confirm existing results. With a direct comparison of baseline and follow-up dataset, the progression of upper motor neuron degeneration, reflected in FA decrease, could be captured along the CST and in frontal areas. The involvement of cerebellum in the pathology of ALS, as suspected from functional MRI studies, could be confirmed by a reduced FA (culmen, declive. These structural changes correlated well with disease duration, ALSFRS-R, and physical and executive functions. Conclusion DTI detects changes that are regarded as prominent features of ALS and thus, shows promise in its function as a biomarker. Using the technique herein, we could demonstrate DTI changes at follow-up which correlated well with clinical progression.

  3. Impaired Perception of Emotional Expression in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Oh, Seong Il; Oh, Ki Wook; Kim, Hee Jin; Park, Jin Seok; Kim, Seung Hyun

    2016-07-01

    The increasing recognition that deficits in social emotions occur in amyotrophic lateral sclerosis (ALS) is helping to explain the spectrum of neuropsychological dysfunctions, thus supporting the view of ALS as a multisystem disorder involving neuropsychological deficits as well as motor deficits. The aim of this study was to characterize the emotion perception abilities of Korean patients with ALS based on the recognition of facial expressions. Twenty-four patients with ALS and 24 age- and sex-matched healthy controls completed neuropsychological tests and facial emotion recognition tasks [ChaeLee Korean Facial Expressions of Emotions (ChaeLee-E)]. The ChaeLee-E test includes facial expressions for seven emotions: happiness, sadness, anger, disgust, fear, surprise, and neutral. The ability to perceive facial emotions was significantly worse among ALS patients performed than among healthy controls [65.2±18.0% vs. 77.1±6.6% (mean±SD), p=0.009]. Eight of the 24 patients (33%) scored below the 5th percentile score of controls for recognizing facial emotions. Emotion perception deficits occur in Korean ALS patients, particularly regarding facial expressions of emotion. These findings expand the spectrum of cognitive and behavioral dysfunction associated with ALS into emotion processing dysfunction.

  4. Tongue movements and their acoustic consequences in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Yunusova, Yana; Green, Jordan R; Greenwood, Lauren; Wang, Jun; Pattee, Gary L; Zinman, Lorne

    2012-01-01

    The relations between acoustic measures and their articulatory bases have rarely been tested in dysarthria but are important for diagnostic and treatment purposes. We tested the association between acoustic measures of F2 range and F2 slope with kinematic measures of tongue movement displacement and speed in individuals with amyotrophic lateral sclerosis (ALS) and healthy controls speaking at normal and slow rates. Relations between acoustic and kinematic measures and speech intelligibility were examined. As healthy controls reduced their speaking rate, their F2 slopes and movement speeds decreased. In talkers with ALS, acoustic and kinematic variables were associated with changes in speaking rate, characteristic of disease progression. Participants with slow rate had shallower F2 slopes and slower movement speeds than those with normal rate. Relations between F2 range and tongue displacement were weaker. F2 slope, displacement, and duration were correlated with speech intelligibility most consistently. Findings suggested that F2 slope is a useful marker for tracking disease progression in ALS. F2 slope reflects changes in tongue function with disease progression and is linked to speech intelligibility. Changes in movement speed, however, might be the earliest sign of disease in the tongue. Copyright © 2012 S. Karger AG, Basel.

  5. Blood Lead, Bone Turnover, and Survival in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Fang, Fang; Peters, Tracy L; Beard, John D; Umbach, David M; Keller, Jean; Mariosa, Daniela; Allen, Kelli D; Ye, Weimin; Sandler, Dale P; Schmidt, Silke; Kamel, Freya

    2017-11-01

    Blood lead and bone turnover may be associated with the risk of amyotrophic lateral sclerosis (ALS). We aimed to assess whether these factors were also associated with time from ALS diagnosis to death through a survival analysis of 145 ALS patients enrolled during 2007 in the National Registry of Veterans with ALS. Associations of survival time with blood lead and plasma biomarkers of bone resorption (C-terminal telopeptides of type I collagen (CTX)) and bone formation (procollagen type I amino-terminal peptide (PINP)) were estimated using Cox models adjusted for age at diagnosis, diagnostic certainty, diagnostic delay, site of onset, and score on the Revised ALS Functional Rating Scale. Hazard ratios were calculated for each doubling of biomarker concentration. Blood lead, plasma CTX, and plasma PINP were mutually adjusted for one another. Increased lead (hazard ratio (HR) = 1.38; 95% confidence interval (CI): 1.03, 1.84) and CTX (HR = 2.03; 95% CI: 1.42, 2.89) were both associated with shorter survival, whereas higher PINP was associated with longer survival (HR = 0.59; 95% CI: 0.42, 0.83), after ALS diagnosis. No interactions were observed between lead or bone turnover and other prognostic indicators. Lead toxicity and bone metabolism may be involved in ALS pathophysiology. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  6. Investigating cell death mechanisms in Amyotrophic lateral sclerosis using transcriptomics

    Directory of Open Access Journals (Sweden)

    Paul Roy Heath

    2013-12-01

    Full Text Available Amyotrophic lateral sclerosis is a motor neuron disease characterised by degeneration and loss of upper and lower motor neurons from the motor cortex, brainstem and spinal cord although evidence is suggesting that there is further involvement of other cell types in the surrounding tissue. Transcriptomic analysis by gene expression profiling using microarray technology has enabled the determination of patterns of cell death in the degenerating tissues. This work has examined gene expression at the level of the tissue and individual cell types in both sporadic and familial forms of the disease. In addition, further studies have examined the differential vulnerability of neuronal cells in different regions of the central nervous system. Model systems have also provided further information to help unravel the mechanisms that lead to death of the motor neurons in disease and also provided novel insights. In this review we shall describe the methods that have been used in these investigations and describe how they have contributed to our knowledge of the cell death mechanisms in ALS.

  7. Financial cost of amyotrophic lateral sclerosis: a case study.

    Science.gov (United States)

    Obermann, M; Lyon, M

    2015-03-01

    There are only a few recently published reports of the cost of amyotrophic lateral sclerosis (ALS) care in the United States. Our objectives were to: 1) report annual and disease-duration costs; 2) provide costs related to specific care and services; 3) present costs by payor; and 4) identify strategies and resources that can be offered to patients to assist with the financial burden of ALS. Over a 10-year period (2001-2010), all expenses related to the cost of care for an individual patient were collected concurrently and then analyzed in 2012. Results showed that total disease-duration costs were $1,433,992 (85% paid by insurance, 9% paid by family, 6% paid by charities). The highest costs were for in-home caregivers ($669,150), ventilation ($212,430) and hospital care ($114,558). In conclusion, this case study illustrates costs of care for ALS as a burden for patients that may impact treatment decisions. Charity organizations and insurance case-managers provide services to patients that can help reduce this burden. Costs for specific services as well as resources identified by this study offer physicians and other healthcare providers data-based cost of care information and strategies to share with their patients.

  8. Dysphagia in amyotrophic lateral sclerosis: prevalence and clinical findings.

    Science.gov (United States)

    Ruoppolo, G; Schettino, I; Frasca, V; Giacomelli, E; Prosperini, L; Cambieri, C; Roma, R; Greco, A; Mancini, P; De Vincentiis, M; Silani, V; Inghilleri, M

    2013-12-01

    To characterize swallowing deficits in amyotrophic lateral sclerosis (ALS); investigate the delay in dysphagia onset; estimate correlations between dysphagia severity and patients' functional status; identify the symptom(s) most likely to predict dysphagia. A group of 49 consecutive patients with ALS, 14 with bulbar onset and 35 with spinal onset, underwent swallowing evaluation including bedside and fiberoptic endoscopic examination to detect dysphagia. Patients with dysphagia were more likely than those without to have bulbar onset ALS (P = 0.02); more severely impaired chewing (P = 0.01); and tongue muscle deficits (P = 0.001). The only variable measured at first examination significantly associated with dysphagia was a more than mild tongue muscle deficit. The only variable useful in predicting dysphagia was a chewing deficit. In 10 of the 49 patients studied, swallowing evaluation disclosed an impaired cough reflex. Dysphagia in patients with ALS correlates significantly with bulbar onset and with oral swallowing impairment. Fiberoptic swallowing evaluation is a useful tool for detecting swallowing deficits and laryngeal sensitivity in patients with ALS. An impaired cough reflex is an unexpected finding in many patients with ALS. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Oropharyngeal dysphagia in amyotrophic lateral sclerosis alters quality of life.

    Science.gov (United States)

    Paris, G; Martinaud, O; Petit, A; Cuvelier, A; Hannequin, D; Roppeneck, P; Verin, E

    2013-03-01

    Dysphagia is one of the most important complications encountered in amyotrophic lateral sclerosis (ALS). Our aim was to determine whether oropharyngeal dysphagia impacted the quality of life (QoL) of patients with ALS. Thirty consecutive patients were recruited (31-82 years, 18 men). Swallowing function was evaluated using a standardised videofluoroscopic barium swallow. All the patients completed a specific questionnaire on quality of life in dysphagia (SWAL-QoL) immediately after the videofluoroscopy. The results of dysphagia outcome severity scale separated 14 patients with oropharyngeal dysphagia and 16 with normal swallowing function. There was no difference in the average age, weight and body mass index of the two groups (dysphagic patients: 68 ± 11 kg versus non-dysphagic patients: 69 ± 14 kg). Most of the dysphagic patients had a bulbar affection based on their Norris scores which determine the importance of cranial nerves illness (20 ± 8), significantly lower than those of the non-dysphagic patients (35 ± 5) (P quality of life questionnaire revealed that the dysphagic patients had significant burden (P dysphagia (P dysphagia which impacted directly mental health (P life (P dysphagia is a common symptom accompanying ALS, which alters the patient's QoL, especially social health. © 2012 Blackwell Publishing Ltd.

  10. Apathy in amyotrophic lateral sclerosis: insights from Dimensional Apathy Scale.

    Science.gov (United States)

    Santangelo, Gabriella; Siciliano, Mattia; Trojano, Luigi; Femiano, Cinzia; Monsurrò, Maria Rosaria; Tedeschi, Gioacchino; Trojsi, Francesca

    2017-08-01

    Apathy is associated with cognitive decline and worse survival in amyotrophic lateral sclerosis (ALS); an accurate evaluation of this aspect is relevant in clinical settings. The aims of this study are to evaluate the prevalence of apathy in a large ALS sample, using published diagnostic criteria, and to explore the psychometric properties, the sensitivity and the specificity of the Dimensional Apathy Scale (DAS) as a screening tool for apathy. One hundred and thirty-one patients underwent clinical interview based on diagnostic criteria for apathy, DAS, Apathy Evaluation Scale, and assessment of depression, global cognitive functioning, and non-verbal intelligence. According to diagnostic criteria, apathy occurred in 28.2% of the patients. The DAS showed high consistency, convergent, and discriminant validities. Apathetic and non-apathetic patients significantly differed on total DAS and executive and Behavioral/Cognitive Initiation subscales, indicating good criterion validity. Receiver operating characteristics analysis, considering diagnostic criteria for apathy as gold standard, revealed that a score of 26/27 was an optimal cut-off score for the identification of apathy. The DAS is a valid screening tool for apathy and its aspects in ALS through limiting the impact of physical disability. Executive and behavioral/cognitive aspects of apathy, rather than emotional aspects, are more frequent in ALS.

  11. Apathy is associated with poor prognosis in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Caga, J; Turner, M R; Hsieh, S; Ahmed, R M; Devenney, E; Ramsey, E; Zoing, M C; Mioshi, E; Kiernan, M C

    2016-05-01

    Apathy is the most commonly reported behavioural change in amyotrophic lateral sclerosis (ALS). However, the degree to which it affects prognosis and overlaps with depression in this population is unknown. The present study examined the relationship between level of apathy, mortality and survival time and whether apathy was linked to specific symptom clusters of depression. A cohort of 76 consecutive ALS patients attending specialized multidisciplinary clinics were classified according to level of apathy. The effects of clinical factors and apathy on survival time were analysed using univariate and multivariate methods. The majority of patients with moderate to severe apathy died during the study (P = 0.003) and had a median survival time of 21.7 months, considerably shorter than patients with mild apathy (46.9 months) and no apathy (51.9 months) (P = 0.0001). Apathy remained a significant predictor of survival even after controlling for clinical factors and symptom duration at the time of study entry (hazard ratio 3.8, 95% confidence interval 1.9-7.5, P = 0.0001). Depression with demoralization was not associated with level of apathy (P = 0.172) whereas depression with anhedonia was more common in patients with apathy than in those without apathy (P = 0.006). The presence of severe apathy is an independent, negative prognostic factor in ALS. © 2016 EAN.

  12. A(a)LS: Ammonia-induced amyotrophic lateral sclerosis.

    Science.gov (United States)

    Parekh, Bhavin

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a dreadful, devastating and incurable motor neuron disease. Aetiologically, it is a multigenic, multifactorial and multiorgan disease. Despite intense research, ALS pathology remains unexplained. Following extensive literature review, this paper posits a new integrative explanation. This framework proposes that ammonia neurotoxicity is a main player in ALS pathogenesis. According to this explanation, a combination of impaired ammonia removal- mainly because of impaired hepatic urea cycle dysfunction-and increased ammoniagenesis- mainly because of impaired glycolytic metabolism in fast twitch skeletal muscle-causes chronic hyperammonia in ALS. In the absence of neuroprotective calcium binding proteins (calbindin, calreticulin and parvalbumin), elevated ammonia-a neurotoxin-damages motor neurons. Ammonia-induced motor neuron damage occurs through multiple mechanisms such as macroautophagy-endolysosomal impairment, endoplasmic reticulum (ER) stress, CDK5 activation, oxidative/nitrosative stress, neuronal hyperexcitability and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins' loss, owing to either ER stress and/or impaired oxidative metabolism, determines clinical variability of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington's disease and Parkinsonism.

  13. Abnormalities of satellite cells function in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Pradat, Pierre-François; Barani, Aude; Wanschitz, Julia; Dubourg, Odile; Lombès, Anne; Bigot, Anne; Mouly, Vincent; Bruneteau, Gaelle; Salachas, François; Lenglet, Timothée; Meininger, Vincent; Butler-Browne, Gillian

    2011-07-01

    Abstract Amyotrophic lateral sclerosis (ALS) is characterized by progressive denervation leading to muscle atrophy prevented, during the early phase, by compensatory reinnervation. Little is known about muscle fibre regeneration capacity in ALS. We have carried out in vivo and in vitro investigation of skeletal muscle in ALS. Seven ALS patients underwent a deltoid muscle biopsy. Immunohistochemical analysis revealed various degrees of denervation- and reinnervation-related changes in the ALS muscle biopsies including satellite cells (SCs) activation and regenerating fibres. Only 3/7 primary cultures of ALS muscle cells were successfully established and had sufficient myogenicity, as assessed by desmin positivity, to be used without further purification. This was in contrast with the cultures derived from control muscles, predominantly desmin-positive cells. Although capable to proliferate in vitro, ALS-derived SCs presented an abnormal senescent-like morphology. Markers of senescence, including senescent-associated (SA)-βGal activity and p16 expression, were increased. Furthermore, ALS-derived SCs were also unable to fully differentiate in vitro as shown by abnormal myotubes morphology and reduced MHC isoform expression, compared to control myotubes. Our study suggests that SC function is altered in ALS. This could limit the efficacy of compensatory processes and therefore could contribute to the progression of muscle atrophy and weakness.

  14. Meta-analysis of social cognition in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Bora, Emre

    2017-03-01

    Amyotrophic lateral sclerosis (ALS) is associated with executive dysfunction and behavioural impairment. Recent studies suggested that social cognitive deficits might also be a prominent feature of ALS. Current meta-analysis aimed to summarize available evidence for deficits in social cognition including theory of mind (ToM) and emotion recognition in ALS. In this meta-analysis of 15 studies, facial emotion recognition and ToM performances of 389 patients with ALS and 471 healthy controls were compared. ALS was associated with significant impairments with medium effect sizes in ToM (d = .65) and facial emotion recognition (d = .69). Among individual emotions recognition of disgust and surprise were particularly impaired. Deficits in perspective taking (d = .73) aspects of ToM (ToM-PT) was more pronounced in comparison to decoding (d = .28) aspects of ToM (ToM-decoding). The severity of social cognitive impairment was similar to level of executive dysfunction and there was a significant relationship between social cognition and executive dysfunction. Deficits in social cognition are part of the cognitive phenotype of ALS. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. [Amyotrophic lateral sclerosis in literature, cinema and television].

    Science.gov (United States)

    Collado-Vázquez, Susana; Carrillo, Jesús María

    2014-07-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a progressive course that affects the corticospinal and spinal cord motor neurons, the main manifestations of which are muscular weakness, amyotrophy and hyperreflexia. It has an incidence of 0.4-2.4 cases/100,000 inhabitants/year, and a prevalence of 4-6 cases/100,000 inhabitants. It is more frequent in adult males over 50 years of age. A number of different neurological diseases have been portrayed in literature, cinema and television, including ALS, which has been presented correctly and realistically. To analysis how literature, cinema and television have addressed ALS. Several different literary works have dealt with ALS, such as El desencuentro, Lou Gehrig: the luckiest man or Tuesdays with Morrie; the cinema has also depicted this disease in films such as The pride of the Yankees, My love beside me (closer to Heaven) or Right to die; and on television this disease has been shown in series, documentaries and television films, such as: Tuesdays with Morrie, Jenifer or A love affair: the Eleanor and Lou Gehrig Story. Most of the works are of a biographical and testimonial nature, and portray the disease realistically, with the intention of making ALS more widely known and raising the population's awareness about the condition. Literature, cinema and television have portrayed ALS in a realistic and believable manner, unlike some other diseases of a neurological origin.

  16. The epidemiology of amyotrophic lateral sclerosis in Reggio Emilia, Italy.

    Science.gov (United States)

    Bonvicini, Francesca; Vinceti, Marco; Marcello, Norina; Rodolfi, Rossella; Rinaldi, Manuela

    2008-12-01

    Incidence and mortality rates of amyotrophic lateral sclerosis (ALS) vary between countries, and in some studies appear to increase over time. We performed a study to assess ALS incidence in a northern Italy area over a 10-year period. We identified the new cases of probable or definite ALS diagnosed among residents in Reggio Emilia province between 1996 and 2005 using several sources of data, such as death certificates, clinical records, hospital discharge registers and drug prescriptions. A total of 94 newly-diagnosed patients were identified. The average standardized incidence in the period was 2.0 and 1.0 cases/100,000/year, using the Italian and the world population, respectively, as reference. There was no variation in rates over time. Incidence was 1.3 in males and 0.8 in females. No cases were observed in patients under 35 years of age. Incidence increased after the age of 55 years, reaching a peak in the group aged 70-74 years and declining thereafter. We concluded that ALS incidence in this population was similar to that observed in other Italian regions and European countries, and no variation was identified during the study period.

  17. Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery.

    Directory of Open Access Journals (Sweden)

    Katrina Gwinn

    2007-12-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is the most common form of motor neuron disease (MND. It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA, phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.

  18. Myasthenia gravis and amyotrophic lateral sclerosis: A pathogenic overlap.

    Science.gov (United States)

    Gotaas, Håvard Torvik; Skeie, Geir Olve; Gilhus, Nils Erik

    2016-06-01

    The aim was to examine potential joint disease mechanisms for myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) through the examination of long-term patient cohorts for comorbidity. Recent studies support early involvement of the neuromuscular junction in ALS patients with subsequent degeneration of motor neurons. Medical records at Haukeland University Hospital from 1987 to 2012 were examined for International Classification of Diseases diagnostic codes for MG and ALS. Sera were re-tested for antibodies to acetylcholine receptor, titin, MuSK and GM1. We report one patient with both MG and ALS, and another 3 patients with suggestive evidence of both conditions. This is far more than expected from prevalence and incidence figures in this area if the disorders were unrelated. Our data suggest that immunological mechanisms in the neuromuscular junction are relevant in ALS pathogenesis. Attention should be given to possible therapeutic targets in the neuromuscular junction and muscle in ALS patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Management of dysphagia in Parkinson's disease and amyotrophic lateral sclerosis.

    Science.gov (United States)

    Luchesi, Karen Fontes; Kitamura, Satoshi; Mourão, Lucia Figueiredo

    2013-01-01

    To describe swallowing management in patients with amyotrophic lateral sclerosis (ALS) and Parkinson' disease (PD), to investigate whether physiopathology determines the choice of therapeutic approaches, and to investigate whether the disease duration modifies the therapeutic approaches. This is a long-term study comprising 24 patients with idiopathic PD and 27 patients with ALS. The patients were followed-up in a dysphagia outpatient clinic between 2006 and 2011. The patients underwent clinic evaluation and Fiberoptic Endoscopic Evaluation of Swallowing, Functional Oral Intake Scale, and therapeutic intervention every 3 months. The swallowing management was based on orientation about the adequate food consistency and volume, besides the necessary maneuvers or exercises to improve swallowing functionality. An exploratory analysis of data was used to investigate associations between the groups of disease (PD or ALS) and clinic aspects and to know about the association between the groups of diseases and the application of maneuver or exercises over the follow-up. The most frequent recommended maneuvers in PD were bolus effect (83.3%), bolus consistency (79.2%), and swallowing frequency (79%). To patients with ALS, the bolus consistency (92%) and the bolus effect (74.1%) were more recommended. Strengthening-tongue (p=0.01), tongue control (p=0.05), and vocal exercises (pdiseases. The physiopathology of the diseases determined the choice of therapeutic approaches. The disease duration of the patients did not interfere directly in the therapeutic approaches.

  20. Concurrent multiple sclerosis and amyotrophic lateral sclerosis: where inflammation and neurodegeneration meet?

    Directory of Open Access Journals (Sweden)

    Li Grace

    2012-01-01

    Full Text Available Abstract The concurrence of multiple sclerosis (MS and amyotrophic lateral sclerosis (ALS is exceedingly rare and the pathological features have not been examined extensively. Here we describe the key pathological features of a 40 year old man with pathologically confirmed concurrent MS and ALS. This is the most pathologically illustrative case of coincident MS and ALS demonstrating inflammatory and neurodegenerative features characteristic of each disease, and is the first to exhibit the presence of TDP-43 inclusions in this clinical entity. The intricate relationship between neuroinflammation and neurodegeneration in these diseases is discussed.

  1. Imaging Findings Associated with Cognitive Performance in Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis

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    Avner Meoded

    2013-08-01

    Full Text Available Introduction: Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS, but it has not been well studied in primary lateral sclerosis (PLS. The aims of this study were to (1 compare cognitive function in PLS to that in ALS patients, (2 explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI metrics of white matter tracts and gray matter volumes, and (3 compare DTI metrics in patients with and without cognitive and behavioral changes. Methods: The Delis-Kaplan Executive Function System (D-KEFS, the Mattis Dementia Rating Scale (DRS-2, and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model. Results: More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores. Conclusion: The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment.

  2. Relevance of the pyramidal syndrome in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Álvarez, N; Díez, L; Avellaneda, C; Serra, M; Rubio, M Á

    Pyramidal signs (hyperreflexia, spasticity, Babinski sign) are essential for the diagnosis of amyotrophic lateral sclerosis (ALS). However, these signs are not always present at onset and may vary over time, besides which their role in disease evolution is controversial. Our goal was to describe which pyramidal signs were present and how they evolved in a cohort of patients with ALS, as well as their role in prognosis. Retrospective analysis of prospectively collected patients diagnosed with ALS in our centre from 1990 to 2015. Of a total of 130 patients with ALS, 34 (26.1%) patients showed no pyramidal signs at the first visit while 15 (11.5%) had a complete pyramidal syndrome. Of those patients without initial pyramidal signs, mean time of appearance of the first signs was 4.5 months. Babinski sign was positive in 64 (49.2%) patients, hyperreflexia in 90 (69.2%) and 22 (16.9%) patients had spasticity. Pyramidal signs tended to remain unchanged over time, although they seem to appear at later stages or even disappear with time in some patients. We found no association between survival and the presence of changes to pyramidal signs, although decreased spasticity was associated with greater clinical deterioration (ALSFR scale) (P<.001). A quarter of patients with ALS initially showed no pyramidal signs and in some cases they even disappear over time. These data support the need for tools that assess the pyramidal tract. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. Lockhart Clarke’s contribution to the description of amyotrophic lateral sclerosis

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    Turner, Martin R.; Swash, Michael; Ebers, George C.

    2011-01-01

    The definition of the clinicopathological entity of amyotrophic lateral sclerosis evolved over half a century. Although the definitive term amyotrophic lateral sclerosis that acknowledged both upper and lower motor neuron involvement was attributed to Jean-Martin Charcot in 1874, his initial case was published nearly a decade earlier; and it is accepted that, from at least the 1830s, several others (including Charles Bell, François-Amilcar Aran and Jean Cruveilhier) had already recognized a progressive lower motor neuron-only syndrome within a broader, clinically-defined group of disorders, termed progressive muscular atrophy. Although William Gowers first grouped the three phenotypes of amyotrophic lateral sclerosis, progressive muscular atrophy and progressive bulbar palsy together as part of the same syndrome, the term motor neuron disease, as an over-arching label, was not suggested until nearly a century later by W. Russell Brain. Augustus Jacob Lockhart Clarke (1817–80) is best known for his descriptions of spinal cord anatomy. However, in two detailed case reports from the 1860s, he carried out rigorous post-mortem neuropathological studies of what appear to be classical cases of amyotrophic lateral sclerosis. Furthermore, he recognized the additional involvement of the corticospinal tracts that distinguished this from progressive muscular atrophy. Several aspects of the exquisite clinical histories documented as part of both studies, one by Charles Bland Radcliffe, resonate with contemporary debates concerning the evolution of disease in amyotrophic lateral sclerosis. These ‘past masters’ still have much to teach us. PMID:20576696

  4. Enteroviral Infection: The Forgotten Link to Amyotrophic Lateral Sclerosis?

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    Yuan Chao Xue

    2018-03-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating neurodegenerative disease that primarily attacks motor neurons in the brain and spinal cord, leading to progressive paralysis and ultimately death. Currently there is no effective therapy. The majority of ALS cases are sporadic, with no known family history; unfortunately the etiology remains largely unknown. Contribution of Enteroviruses (EVs, a family of positive-stranded RNA viruses including poliovirus, coxsackievirus, echovirus, enterovirus-A71 and enterovirus-D68, to the development of ALS has been suspected as they can target motor neurons, and patients with prior poliomyelitis show a higher risk of motor neuron disease. Multiple efforts have been made to detect enteroviral genome in ALS patient tissues over the past two decades; however the clinical data are controversial and a causal relationship has not yet been established. Recent evidence from in vitro and animal studies suggests that enterovirus-induced pathology remarkably resembles the cellular and molecular phenotype of ALS, indicating a possible link between enteroviral infection and ALS pathogenesis. In this review, we summarize the nature of enteroviral infection, including route of infection, cells targeted, and viral persistence within the central nervous system (CNS. We review the molecular mechanisms underlying viral infection and highlight the similarity between viral pathogenesis and the molecular and pathological features of ALS, and finally, discuss the potential role of enteroviral infection in frontotemporal dementia (FTD, a disease that shares common clinical, genetic, and pathological features with ALS, and the significance of anti-viral therapy as an option for the treatment of ALS.

  5. Cognitive phenotypes of sequential staging in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Lulé, Dorothée; Böhm, Sarah; Müller, Hans-Peter; Aho-Özhan, Helena; Keller, Jürgen; Gorges, Martin; Loose, Markus; Weishaupt, Jochen H; Uttner, Ingo; Pinkhardt, Elmar; Kassubek, Jan; Del Tredici, Kelly; Braak, Heiko; Abrahams, Sharon; Ludolph, Albert C

    2018-04-01

    Sequential spread of TDP-43 load in the brain may be a pathological characteristic of amyotrophic lateral sclerosis (ALS). Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) based marker of this pathological feature. Cognitive deficits known to be present in a subset of ALS patients might act as an additional in vivo clinical marker of disease spread. N = 139 patients with ALS were tested with the Edinburgh Cognitive and Behavioural ALS screen (ECAS) in addition to DTI brain measures of pathological spread. Executive function, memory and disinhibited behaviour were selected for Cognitive-Staging criteria, as these cognitive functions are attributed to cerebral areas analogous to the pattern of MRI markers of TDP-43 pathology. ROC curve analyses were performed to define cut-off scores for cognitive stages 2 (executive function), stage 3 (disinhibited behaviour) and stage 4 (memory), and staging was performed according to the cognitive profile subsequently. Associations of Cognitive-Staging (stage 2-4) and MRI-Staging measures were determined. In total, 77 patients (55%) performed below ROC cut-off scores in either executive function or memory or both and/or were reported to have disinhibited behaviour which permitted Cognitive-Staging. The cognitive profile of patients with discrete MRI stages 2-4 correlated significantly with DTI parameters. For those patients with cognitive impairment, there was a high congruency between MRI and Cognitive-Staging with high specificity and sensitivity of executive functions for MRI stage 2, disinhibited behaviour for MRI stage 3 and moderate of memory for MRI stage 4. Cognitive impairment follows specific patterns in ALS and these patterns can be used for Cognitive-Staging with a high specificity compared to MRI-Staging. For the individual, cognitive screening is a fast and easy to apply measurement of cerebral function giving valuable information in a clinical context. Copyright © 2018 Elsevier Ltd. All

  6. Advances in the application of MRI to amyotrophic lateral sclerosis

    Science.gov (United States)

    Turner, Martin R; Modo, Michel

    2011-01-01

    Importance of the field With the emergence of therapeutic candidates for the incurable and rapidly progressive neurodegenerative condition of amyotrophic lateral sclerosis (ALS), it will be essential to develop easily obtainable biomarkers for diagnosis, as well as monitoring, in a disease where clinical examination remains the predominant diagnostic tool. Magnetic resonance imaging (MRI) has greatly developed over the past thirty years since its initial introduction to neuroscience. With multi-modal applications, MRI is now offering exciting opportunities to develop practical biomarkers in ALS. Areas covered in this review The historical application of MRI to the field of ALS, its state-of-the-art and future aspirations will be reviewed. Specifically, the significance and limitations of structural MRI to detect gross morphological tissue changes in relation to clinical presentation will be discussed. The more recent application of diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), functional and resting-state MRI (fMRI & R-fMRI) will be contrasted in relation to these more conventional MRI assessments. Finally, future aspirations will be sketched out in providing a more disease mechanism-based molecular MRI. What the reader will gain This review will equip the reader with an overview of the application of MRI to ALS and illustrate its potential to develop biomarkers. This discussion is exemplified by key studies, demonstrating the strengths and limitations of each modality. The reader will gain an expert opinion on both the current and future developments of MR imaging in ALS. Take home message MR imaging generates potential diagnostic, prognostic and therapeutic monitoring biomarkers of ALS. The emerging fusion of structural, functional and potentially molecular imaging will improve our understanding of wider cerebral connectivity and holds the promise of biomarkers sensitive to the earliest changes. PMID:21516259

  7. Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach

    Directory of Open Access Journals (Sweden)

    Hogden A

    2017-05-01

    Full Text Available Anne Hogden,1 Geraldine Foley,2 Robert D Henderson,3 Natalie James,4 Samar M Aoun5 1Australian Institute of Health Innovation, Macquarie University, Sydney, NSW, Australia; 2Discipline of Occupational Therapy, School of Medicine, Trinity College Dublin, the University of Dublin, Republic of Ireland; 3Neurology, Royal Brisbane & Women’s Hospital, Brisbane, QLD, 4Motor Neurone Disease (MND Service, Communication and Assistive Technology (CAT Clinic, St Joseph’s Hospital, St Vincent’s Health Network, Sydney, NSW, 5School of Nursing, Midwifery and Paramedicine, Faculty of Health Sciences, Curtin University, Perth, WA, Australia Abstract: Amyotrophic lateral sclerosis (ALS is a progressive neurodegenerative disease, leading to death within an average of 2–3 years. A cure is yet to be found, and a single disease-modifying treatment has had a modest effect in slowing disease progression. Specialized multidisciplinary ALS care has been shown to extend survival and improve patients’ quality of life, by providing coordinated interprofessional care that seeks to address the complex needs of this patient group. This review examines the nature of specialized multidisciplinary care in ALS and draws on a broad range of evidence that has shaped current practice. The authors explain how multidisciplinary ALS care is delivered. The existing models of care, the role of palliative care within multidisciplinary ALS care, and the costs of formal and informal care are examined. Critical issues of ALS care are then discussed in the context of the support rendered by multidisciplinary-based care. The authors situate the patient and family as key stakeholders and decision makers in the multidisciplinary care network. Finally, the current challenges to the delivery of coordinated interprofessional care in ALS are explored, and the future of coordinated interprofessional care for people with ALS and their family caregivers is considered. Keywords: quality of life

  8. Neurodegenerative and psychiatric diseases among families with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Longinetti, Elisa; Mariosa, Daniela; Larsson, Henrik; Ye, Weimin; Ingre, Caroline; Almqvist, Catarina; Lichtenstein, Paul; Piehl, Fredrik; Fang, Fang

    2017-08-08

    To estimate risks of neurodegenerative and psychiatric diseases among patients with amyotrophic lateral sclerosis (ALS) and their families. We conducted a register-based nested case-control study during 1990-2013 in Sweden to assess whether patients with ALS had higher risks of other neurodegenerative and psychiatric diseases before diagnosis. We included 3,648 patients with ALS and 36,480 age-, sex-, and county of birth-matched population controls. We further conducted a follow-up study of the cases and controls to assess the risks of other neurodegenerative and psychiatric diseases after ALS diagnosis. To assess the potential contribution of familial factors, we conducted similar studies for the relatives of patients with ALS and their controls. Individuals with previous neurodegenerative or psychiatric diseases had a 49% increased risk of ALS (odds ratio 1.49, 95% confidence interval 1.35-1.66) compared to individuals without these diseases. After diagnosis, patients with ALS had increased risks of other neurodegenerative or psychiatric diseases (hazard ratio 2.90, 95% confidence interval 2.46-3.43) compared to individuals without ALS. The strongest associations were noted for frontotemporal dementia, Parkinson disease, other dementia, Alzheimer disease, neurotic disorders, depression, stress-related disorders, and drug abuse/dependence. First-degree relatives of patients with ALS had higher risk of neurodegenerative diseases, whereas only children of patients with ALS had higher risk of psychiatric disorders, compared to relatives of the controls. Familial aggregation of ALS and other neurodegenerative diseases implies a shared etiopathogenesis among all neurodegenerative diseases. The increased risk of psychiatric disorders among patients with ALS and their children might be attributable to nonmotor symptoms of ALS and severe stress response toward the diagnosis. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the

  9. Multidimensional apathy and executive dysfunction in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Radakovic, Ratko; Stephenson, Laura; Newton, Judith; Crockford, Christopher; Swingler, Robert; Chandran, Siddharthan; Abrahams, Sharon

    2017-09-01

    Apathy and cognitive dysfunction are prominent symptoms of Amyotrophic lateral sclerosis (ALS). More specifically ALS patients show increased Initiation apathy-a lack of motivation for self-generation of thoughts as assessed by the Dimensional Apathy Scale. This study aimed to investigate the cognitive underpinnings of apathy subtypes in ALS. We hypothesized that increased Initiation apathy would be associated deficits on tests of intrinsic response generation, such as verbal fluency. We also explored the relationship of other apathy subtypes to cognitive processes, in particular emotional apathy with emotional and social cognition deficits and executive apathy with planning and goal management deficits. ALS patients, and their carers (N = 30), and healthy matched controls, and their informants (N = 29) were recruited. All participants completed self- and informant/carer-rated Dimensional Apathy Scale, to quantify apathy subtypes (Executive, Emotional and Initiation), along with standard apathy and depression measures. Patients and controls completed the Edinburgh Cognitive and behavioural ALS Screen, and a comprehensive neuropsychological battery including emotional recognition, social cognition, intrinsic response generation tasks (verbal fluency and random number generation) and a new ecologically valid, computerised measure of planning and goal management. The results demonstrated that increased Initiation apathy was the only significantly elevated subtype in ALS (self-rated p < .05, informant/carer-rated p < .01). Initiation apathy was found to be significantly associated with verbal fluency deficit, while Emotional apathy was significantly associated with emotional recognition deficits. No associations were found between apathy subtypes and depression or in controls. This is the first study to show specific associations between apathy subtypes (Emotional and Initiation) and executive and emotional cognitive dysfunction, indicating possible distinct

  10. Amyloid- and FDG-PET imaging in amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Matias-Guiu, Jordi A.; Pytel, Vanesa; Galan, Lucia; Valles-Salgado, Maria; Guerrero, Antonio; Moreno-Ramos, Teresa; Matias-Guiu, Jorge [Hospital Clinico San Carlos, San Carlos Institute for Health Research (IdISSC), Universidad Complutense de Madrid, Department of Neurology, Madrid (Spain); Cabrera-Martin, Maria Nieves; Carreras, Jose Luis [Hospital Clinico San Carlos, San Carlos Institute for Health Research (IdISSC), Universidad Complutense de Madrid, Department of Nuclear Medicine, Madrid (Spain)

    2016-10-15

    We aimed to study brain metabolism and presence of beta-amyloid deposits using positron emission tomography (PET) in patients with amyotrophic lateral sclerosis (ALS). This prospective cross-sectional study included 18 patients with definite or probable ALS according to the revised El Escorial diagnostic criteria, and 24 healthy controls. Patients underwent neurological and neuropsychological assessments, PET with {sup 18}F-fluorodeoxyglucose (FDG), and amyloid-PET with {sup 18}F-florbetaben. Patients with ALS showed hypometabolism in the frontal area and hypermetabolism in the cerebellum compared to healthy controls. Four patients (22 %) displayed cognitive impairment and decreased metabolism in the frontal area extending bilaterally to the parietal regions, and increased metabolism in the posterior area of the cerebellum. In patients with no cognitive impairment, metabolism was lower in the left superior frontal gyrus and higher in the anterior and posterior lobes of the cerebellum. In the individual analysis, six patients (35 %) displayed more anterior involvement with hypometabolism affecting the superior frontal, medial, and inferior gyri; six patients (35 %) exhibited a more posterior pattern with hypometabolism in the precentral and postcentral gyri and in the superior and inferior parietal lobules; two patients (11 %) showed a mixed pattern; and three patients (17 %) showed no alterations in brain metabolism. Three (16 %) showed increased {sup 18}F-florbetaben uptake compared to controls. We have identified two main patterns of brain metabolism with an association to cognitive status. Only a subgroup of patients showed an increased uptake of the amyloid tracer. Our results suggest that ALS is heterogeneous from a clinical, metabolic, and molecular standpoint. (orig.)

  11. Misregulation of iron homeostasis in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Anna Gajowiak

    2016-06-01

    Full Text Available Iron is essential for all mammalian cells, but it is toxic in excess. Our understanding of molecular mechanisms ensuring iron homeostasis at both cellular and systemic levels has dramatically increased over the past 15 years. However, despite major advances in this field, homeostatic regulation of iron in the central nervous system (CNS requires elucidation. It is unclear how iron moves in the CNS and how its transfer to the CNS across the blood-brain and the blood-cerebrospinal fluid barriers, which separate the CNS from the systemic circulation, is regulated. Increasing evidence indicates the role of iron dysregulation in neuronal cell death observed in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS. ALS is a progressive neurodegenerative disorder characterized by selective cortical czynand spinal motor neuron dysfunction that results from a complex interplay among various pathogenic factors including oxidative stress. The latter is known to strongly affect cellular iron balance, creating a vicious circle to exacerbate oxidative injury. The role of iron in the pathogenesis of ALS is confirmed by therapeutic effects of iron chelation in ALS mouse models. These models are of great importance for deciphering molecular mechanisms of iron accumulation in neurons. Most of them consist of transgenic rodents overexpressing the mutated human superoxide dismutase 1 (SOD1 gene. Mutations in the SOD1 gene constituteone of the most common genetic causes of the inherited form of ALS. However, it should beconsidered that overexpression of the SOD1 gene usually leads to increased SOD1 enzymaticactivity, a condition which does not occur in human pathology and which may itself changethe expression of iron metabolism genes.

  12. Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Claudia Figueroa-Romero

    Full Text Available Amyotrophic lateral sclerosis (ALS is a terminal disease involving the progressive degeneration of motor neurons within the motor cortex, brainstem and spinal cord. Most cases are sporadic (sALS with unknown causes suggesting that the etiology of sALS may not be limited to the genotype of patients, but may be influenced by exposure to environmental factors. Alterations in epigenetic modifications are likely to play a role in disease onset and progression in ALS, as aberrant epigenetic patterns may be acquired throughout life. The aim of this study was to identify epigenetic marks associated with sALS. We hypothesize that epigenetic modifications may alter the expression of pathogenesis-related genes leading to the onset and progression of sALS. Using ELISA assays, we observed alterations in global methylation (5 mC and hydroxymethylation (5 HmC in postmortem sALS spinal cord but not in whole blood. Loci-specific differentially methylated and expressed genes in sALS spinal cord were identified by genome-wide 5mC and expression profiling using high-throughput microarrays. Concordant direction, hyper- or hypo-5mC with parallel changes in gene expression (under- or over-expression, was observed in 112 genes highly associated with biological functions related to immune and inflammation response. Furthermore, literature-based analysis identified potential associations among the epigenes. Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets.

  13. The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Stephanie R Shepheard

    Full Text Available Objective biomarkers for amyotrophic lateral sclerosis would facilitate the discovery of new treatments. The common neurotrophin receptor p75 is up regulated and the extracellular domain cleaved from injured neurons and peripheral glia in amyotrophic lateral sclerosis. We have tested the hypothesis that urinary levels of extracellular neurotrophin receptor p75 serve as a biomarker for both human motor amyotrophic lateral sclerosis and the SOD1(G93A mouse model of the disease. The extracellular domain of neurotrophin receptor p75 was identified in the urine of amyotrophic lateral sclerosis patients by an immuno-precipitation/western blot procedure and confirmed by mass spectrometry. An ELISA was established to measure urinary extracellular neurotrophin receptor p75. The mean value for urinary extracellular neurotrophin receptor p75 from 28 amyotrophic lateral sclerosis patients measured by ELISA was 7.9±0.5 ng/mg creatinine and this was significantly higher (p<0.001 than 12 controls (2.6±0.2 ng/mg creatinine and 19 patients with other neurological disease (Parkinson's disease and Multiple Sclerosis; 4.1±0.2 ng/mg creatinine. Pilot data of disease progression rates in 14 MND patients indicates that p75NTR(ECD levels were significantly higher (p = 0.0041 in 7 rapidly progressing patients as compared to 7 with slowly progressing disease. Extracellular neurotrophin receptor p75 was also readily detected in SOD1(G93A mice by immuno-precipitation/western blot before the onset of clinical symptoms. These findings indicate a significant relation between urinary extracellular neurotrophin receptor p75 levels and disease progression and suggests that it may be a useful marker of disease activity and progression in amyotrophic lateral sclerosis.

  14. TDP-43 pathology in the basal forebrain and hypothalamus of patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Cykowski, Matthew D; Takei, Hidehiro; Schulz, Paul E; Appel, Stanley H; Powell, Suzanne Z

    2014-12-24

    Amyotrophic lateral sclerosis is a neurodegenerative disease characterized clinically by motor symptoms including limb weakness, dysarthria, dysphagia, and respiratory compromise, and pathologically by inclusions of transactive response DNA-binding protein 43 kDa (TDP-43). Patients with amyotrophic lateral sclerosis also may demonstrate non-motor symptoms and signs of autonomic and energy dysfunction as hypermetabolism and weight loss that suggest the possibility of pathology in the forebrain, including hypothalamus. However, this region has received little investigation in amyotrophic lateral sclerosis. In this study, the frequency, topography, and clinical associations of TDP-43 inclusion pathology in the basal forebrain and hypothalamus were examined in 33 patients with amyotrophic lateral sclerosis: 25 men and 8 women; mean age at death of 62.7 years, median disease duration of 3.1 years (range of 1.3 to 9.8 years). TDP-43 pathology was present in 11 patients (33.3%), including components in both basal forebrain (n=10) and hypothalamus (n=7). This pathology was associated with non-motor system TDP-43 pathology (Χ2=17.5, p=0.00003) and bulbar symptoms at onset (Χ2=4.04, p=0.044), but not age or disease duration. Furthermore, TDP-43 pathology in the lateral hypothalamic area was associated with reduced body mass index (W=11, p=0.023). This is the first systematic demonstration of pathologic involvement of the basal forebrain and hypothalamus in amyotrophic lateral sclerosis. Furthermore, the findings suggest that involvement of the basal forebrain and hypothalamus has significant phenotypic associations in amyotrophic lateral sclerosis, including site of symptom onset, as well as deficits in energy metabolism with loss of body mass index.

  15. Dietary BMAA Exposure in an Amyotrophic Lateral Sclerosis Cluster from Southern France

    Science.gov (United States)

    Masseret, Estelle; Banack, Sandra; Boumédiène, Farid; Abadie, Eric; Brient, Luc; Pernet, Fabrice; Juntas-Morales, Raoul; Pageot, Nicolas; Metcalf, James; Cox, Paul; Camu, William

    2013-01-01

    Background Dietary exposure to the cyanotoxin BMAA is suspected to be the cause of amyotrophic lateral sclerosis in the Western Pacific Islands. In Europe and North America, this toxin has been identified in the marine environment of amyotrophic lateral sclerosis clusters but, to date, only few dietary exposures have been described. Objectives We aimed at identifying cluster(s) of amyotrophic lateral sclerosis in the Hérault district, a coastal district from Southern France, and to search, in the identified area(s), for the existence of a potential dietary source of BMAA. Methods A spatio-temporal cluster analysis was performed in the district, considering all incident amyotrophic lateral sclerosis cases identified from 1994 to 2009 by our expert center. We investigated the cluster area with serial collections of oysters and mussels that were subsequently analyzed blind for BMAA concentrations. Results We found one significant amyotrophic lateral sclerosis cluster (p = 0.0024), surrounding the Thau lagoon, the most important area of shellfish production and consumption along the French Mediterranean coast. BMAA was identified in mussels (1.8 µg/g to 6.0 µg/g) and oysters (0.6 µg/g to 1.6 µg/g). The highest concentrations of BMAA were measured during summer when the highest picocyanobacteria abundances were recorded. Conclusions While it is not possible to ascertain a direct link between shellfish consumption and the existence of this ALS cluster, these results add new data to the potential association of BMAA with sporadic amyotrophic lateral sclerosis, one of the most severe neurodegenerative disorder. PMID:24349504

  16. "Understanding my ALS". Experiences and reflections of persons with amyotrophic lateral sclerosis and relatives on participation in peer group rehabilitation

    DEFF Research Database (Denmark)

    Madsen, Louise Sofia; Jeppesen, Jørgen; Handberg, Charlotte

    2018-01-01

    with joint inclusion of persons with amyotrophic lateral sclerosis and relatives. Implications for Rehabilitation Peer group rehabilitation may facilitate an increased and personalised understanding of what it means to live with amyotrophic lateral sclerosis. A programme design with six months of sequential...

  17. Place of death in patients with amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    J. Escarrabill

    2014-07-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a degenerative neurological disorder that affects motor neurons. Involvement of respiratory muscles causes the failure of the ventilator pump with more or less significant bulbar troubles. ALS course is highly variable but, in most cases, this disease entails a very significant burden for patients and caregivers, especially in the end-of-life period.In order to analyze the characteristics of ALS patients who die at home (DH and in hospital (DHosp and to study the variability of clinical practice, a retrospective medical records analysis was performed (n = 77 from five hospitals. Variables: time elapsed since the onset of symptoms and the beginning of ventilation, characteristics of ventilation (device, mask and hours/day, and support devices and procedures. Results: In all, 14% of patients were ventilated by tracheotomy. From the analysis, 57% of patients were of DH. Mean time since the onset of symptoms was 35.93 ± 25.89 months, significantly shorter in patients who DHosp (29.28 ± 19.69 months than DH (41.12 ± 29.04 (p = 0.044. The percentage of patients with facial ventilation is higher in DHosp (11.4% vs 39.4%, p < 0.005.DH or not is related to a set of elements in which health resources, physician attitudes and support resources in the community play a role in the decision-making process. There is great variability between countries and between hospitals in the same country. Given the variability of circumstances in each territory, the place of death in ALS might not be the most important element; more important are the conditions under which the process unfolds. Resumo: A esclerose lateral amiotrófica (ELA é uma perturbação neurológica degenerativa que afeta os neurónios motores. O envolvimento dos músculos respiratórios causa a falha da bomba ventilatória, com problemas bulbares mais ou menos significativos. A evolução da ELA

  18. MOLECULAR STRUCTURE OF AMYOTROPHIC LATERAL SCLEROSIS IN RUSSIAN POPULATION

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    N. Yu. Abramycheva

    2016-01-01

    Full Text Available Materials and methods. 285 Russian patients with amyotrophic lateral sclerosis (ALS including 260 patients with a sporadic form and 25 with a familial form were examined for mutations in SOD1, C9orf72, TARDBP,  ANG and other genes and the presence of associations among polymorphic sites in ATXN2 (polyCAG and VEGF (-2578С/А genes.Molecular genetic analysis was performed using direct sequencing, fragment analysis and real-time polymerase chain reaction. On the last stage, rare ALS candidate genes were evaluated using a next generation sequencing (NGS panel.Results. Total rate of the identified mutations in the examined ALS cohort was 9.5 %. The most frequently observed defects were mutations in the SOD1 (24.0 % in familial ALS and 4.6 % in sporadic ALS and C9orf72 (pathological hexanucleotide repeat expansion was identified in 1.8 % cases of ALS, all sporadic genes. The TARDBP gene didn’t contain any mutations, though in the ALS group deletion c.715-126delG located in intron 5 of the TARDBP gene was significantly over-represented – 38.0 % vs. 26.6 % (χ2 = 13.17; р = 0.002. Mutations in the ANG gene were identified in 1.05 % of ALS patients (all cases were sporadic. In 1 (0.35 % sporadic case a G1082A mutation in the DCTN1 gene was identified. The examined group significantly more frequently carried a risk allele of the ATXN2 gene with an “intermediate” (28–33  number of CAG repeats – 5.0 % vs. 1.7 % in the control group (χ2 = 3.89; р = 0.0486. In Russian ALS patients, an association between the disease and the presence of a risk А-allele and homozygote genotype А/А of -2578С/А polymorphism in the VEGF gene was identified (χ2 = 7.14; р = 0.008 and χ2 = 13.46; р = 0.001 for the rates in the ALS population and in the control population, respectively, which is confirmed by the odds ratio.Conclusion. In the current article, molecular structure of ALS in the Russian population was examined, rates of individual genetic forms

  19. Anti-ganglioside antibodies in amyotrophic lateral sclerosis revisited.

    Directory of Open Access Journals (Sweden)

    Katja Kollewe

    Full Text Available Amyotrophic Lateral Sclerosis (ALS is a devastating neurodegenerative disorder with typical onset in the 5th- 6th decade of life. The hypothesis of an autoimmune origin of ALS receives less attention today, but immunological phenomena still seem to be involved and mechanisms such as protective autoimmunity may be important. Detection of antibodies against a variety of gangliosides has been repeatedly described in ALS-patients by several authors, but widely differing frequencies and titres have been reported. Therefore, we investigated the presence of six common antibodies with a commercially available test panel for GA1, GM1, GM2, GD1a, GD1b and GQ1b in a large group of clinically well-characterized ALS patients and compared them to a collective of 200 healthy blood donors.IgG and IgM antibodies to the six gangliosides asialoGM1 (GA1, GM1, GM2, GD1a, GD1b, GQ1b were determined by GanglioCombi ELISA in sera of 84 ALS patients. Results were expressed as a %-ratio of a highly positive control and categorized as negative (100%. The values obtained from 200 Swiss blood donors served as a reference group.In twenty-two (26.2% ALS-patients elevated anti-ganglioside antibodies could be detected: Taking all subspecific antibodies together, IgG antibodies were found in 9/84 (10.7% and IgM in 15/84 (17.9% patients. There was no correlation between age, gender, site of onset or survival and anti-ganglioside-positive/-negative titres in ALS-patients. No statistically significant difference in the frequency of anti-ganglioside antibodies compared to the group of healthy blood donors was found.Even with this more comprehensive approach, anti-ganglioside antibody frequencies and patterns in our ALS cohort closely resembled the values measured in healthy controls. In accordance with other studies, we did not observe any association of a distinct ALS phenotype with elevated anti-ganglioside antibodies or an impact on survival.

  20. Spatial clustering of amyotrophic lateral sclerosis in Finland at place of birth and place of death

    DEFF Research Database (Denmark)

    Sabel, Clive E.; Boyle, P. J.; Löytönen, M.

    2003-01-01

    Previous evidence for spatial clustering of amyotrophic lateral sclerosis is inconclusive. Studies that have identified apparent clusters have often been based on a small number of cases, which means the results may have occurred by chance processes. Also, most studies have used the geographic...... location at the time of death as the basis for cluster detection, rather than exploring clusters at other points in the life cycle. In this study, the authors examine 1,000 cases of amyotrophic lateral sclerosis distributed throughout Finland who died between June 1985 and December 1995. Using a spatial...

  1. Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: a systematic review

    NARCIS (Netherlands)

    Sutedja, N.A.; Veldink, J.H.; Fischer, K.; Kromhout, H.; Heederik, D.J.J.; Huisman, M.H.B.; Wokke, J.H.J.; van den Berg, L.H.

    2009-01-01

    Environmental exposure to chemicals and metals may contribute to the risk of sporadic amyotrophic lateral sclerosis (ALS). Two systematic reviews of the literature on these topics performed according to the well-established MOOSE guidelines are presented. Literature cited in MEDLINE, EMBASE, CINAHL,

  2. Speech Deterioration in Amyotrophic Lateral Sclerosis (ALS) after Manifestation of Bulbar Symptoms

    Science.gov (United States)

    Makkonen, Tanja; Ruottinen, Hanna; Puhto, Riitta; Helminen, Mika; Palmio, Johanna

    2018-01-01

    Background: The symptoms and their progression in amyotrophic lateral sclerosis (ALS) are typically studied after the diagnosis has been confirmed. However, many people with ALS already have severe dysarthria and loss of adequate speech at the time of diagnosis. Speech-and-language therapy interventions should be targeted timely based on…

  3. Prose memory impairment in amyotrophic lateral sclerosis patients is related to hippocampus volume

    NARCIS (Netherlands)

    Raaphorst, J.; van Tol, M.J.; de Visser, M.; van der Kooi, A.J.; Majoie, C.B.; Van den Berg, L.H.; Schmand, B.; Veltman, D.J.

    2015-01-01

    Background and purpose: Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study, brain atrophy in relation to memory

  4. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

    NARCIS (Netherlands)

    Cirulli, Elizabeth T.; Lasseigne, Brittany N.; Petrovski, Slavé; Sapp, Peter C.; Dion, Patrick A.; Leblond, Claire S.; Couthouis, Julien; Lu, Yi-Fan; Wang, Quanli; Krueger, Brian J.; Ren, Zhong; Keebler, Jonathan; Han, Yujun; Levy, Shawn E.; Boone, Braden E.; Wimbish, Jack R.; Waite, Lindsay L.; Jones, Angela L.; Carulli, John P.; Day-Williams, Aaron G.; Staropoli, John F.; Xin, Winnie W.; Chesi, Alessandra; Raphael, Alya R.; McKenna-Yasek, Diane; Cady, Janet; de Jong, J. M. B. Vianney; Kenna, Kevin P.; Smith, Bradley N.; Topp, Simon; Miller, Jack; Gkazi, Athina; Al-Chalabi, Ammar; van den Berg, Leonard H.; Veldink, Jan; Silani, Vincenzo; Ticozzi, Nicola; Shaw, Christopher E.; Baloh, Robert H.; Appel, Stanley; Simpson, Ericka; Lagier-Tourenne, Clotilde; Pulst, Stefan M.; Gibson, Summer; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Grossman, Murray; Shneider, Neil A.; Chung, Wendy K.; Ravits, John M.; Glass, Jonathan D.; Sims, Katherine B.; van Deerlin, Vivianna M.; Maniatis, Tom; Hayes, Sebastian D.; Ordureau, Alban; Swarup, Sharan; Landers, John; Baas, Frank; Allen, Andrew S.; Bedlack, Richard S.; Harper, J. Wade; Gitler, Aaron D.; Rouleau, Guy A.; Brown, Robert; Harms, Matthew B.; Cooper, Gregory M.; Harris, Tim; Myers, Richard M.; Goldstein, David B.; Hardiman, Orla; McLaughlin, Russell L.; Mazzini, Letizia; Blair, Ian P.; Williams, Kelly L.; Nicholson, Garth A.; Al-Sarraj, Safa; King, Andrew; Scotter, Emma L.; Troakes, Claire; Vance, Caroline; D'alfonso, Sandra; Duga, Stefano; Corrado, Lucia; ten Asbroek, Anneloor L. M. A.; Calini, Daniela; Colombrita, Claudia; Ratti, Antonia; Tiloca, Cinzia; Wu, Zheyang; Asress, Seneshaw; Polak, Meraida; Diekstra, Frank; van Rheenen, Wouter; Danielson, Eric W.; Fallini, Claudia; Keagle, Pamela; Lewis, Elizabeth A.; Kost, Jason; Sorarù, Gianni; Bertolin, Cinzia; Querin, Giorgia; Castellotti, Barbara; Gellera, Cinzia; Pensato, Viviana; Taroni, Franco; Cereda, Cristina; Gagliardi, Stella; Ceroni, Mauro; Lauria, Giuseppe; de Belleroche, Jacqueline; Comi, Giacomo P.; Corti, Stefania; del Bo, Roberto; Turner, Martin R.; Talbot, Kevin; Pall, Hardev; Morrison, Karen E.; Shaw, Pamela J.; Esteban-Pérez, Jesús; García-Redondo, Alberto; Muñoz-Blanco, José Luis

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS

  5. Endogenous female reproductive hormones and the risk of amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    de Jong, Sonja; Huisman, Mark; Sutedja, Nadia; van der Kooi, Anneke; de Visser, Marianne; Schelhaas, Jurgen; van der Schouw, Yvonne; Veldink, Jan; van den Berg, Leonard

    2013-01-01

    The pathogenesis of amyotrophic lateral sclerosis (ALS) is considered to be multifactorial. Several epidemiological studies showed a lower incidence of ALS in women than in men. This suggests a possible protective effect of female reproductive hormones. The aim of this study was to investigate the

  6. Rare and common paraoxonase gene variants in amyotrophic lateral sclerosis patients.

    NARCIS (Netherlands)

    Blitterswijk, M. van; Blokhuis, A.; Es, M.A. van; Vught, P.W. van; Rowicka, P.A.; Schelhaas, H.J.; Kooi, A.J. van der; Visser, M. de; Veldink, J.H.; Berg, L.H. van den

    2012-01-01

    Polymorphisms in the paraoxonase family (PON) have been reported in patients with amyotrophic lateral sclerosis (ALS), but a recent meta-analysis did not show a clear association. Recently, PON mutations have also been identified in ALS patients. In this study, we assessed the frequency of PON

  7. Rare and common paraoxonase gene variants in amyotrophic lateral sclerosis patients

    NARCIS (Netherlands)

    van Blitterswijk, Marka; Blokhuis, Anna; van Es, Michael A.; van Vught, Paul W. J.; Rowicka, Paulina A.; Schelhaas, Helenius J.; van der Kooi, Anneke J.; de Visser, Marianne; Veldink, Jan H.; van den Berg, Leonard H.

    2012-01-01

    Polymorphisms in the paraoxonase family (PON) have been reported in patients with amyotrophic lateral sclerosis (ALS), but a recent meta-analysis did not show a clear association. Recently, PON mutations have also been identified in ALS patients. In this study, we assessed the frequency of PON

  8. Needs of informal caregivers across the caregiving course in amyotrophic lateral sclerosis: a qualitative analysis.

    LENUS (Irish Health Repository)

    Galvin, Miriam

    2018-01-27

    Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a debilitating terminal condition. Informal caregivers are key figures in ALS care provision. The physical, psychological and emotional impact of providing care in the home requires appropriate assistance and support. The objective of this analysis is to explore the needs of informal ALS caregivers across the caregiving course.

  9. Lower motor neuron involvement examined by quantitative electromyography in amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Krarup, Christian

    2011-01-01

    Objective The diagnosis of amyotrophic lateral sclerosis (ALS) includes demonstration of lower motor neuron (LMN) and upper motor neuron (UMN) involvement of bulbar and spinal muscles. Electromyography (EMG) is essential to confirm LMN affection in weak muscles, and to demonstrate changes...

  10. Inclusions of amyotrophic lateral sclerosis-linked superoxide dismutase in ventral horns, liver, and kidney

    DEFF Research Database (Denmark)

    Jonsson, P.A.; Bergemalm, D.; Andersen, P.M.

    2008-01-01

    Mutant superoxide dismutases type 1 (SOD1s) cause amyotrophic lateral sclerosis by an unidentified toxic property. In a patient carrying the G127X truncation mutation, minute amounts of SOD1 were found in ventral horns using a mutant-specific antibody. Still, both absolute levels and ratios versus...

  11. Skeletal Muscle Remodelling as a Function of Disease Progression in Amyotrophic Lateral Sclerosis

    DEFF Research Database (Denmark)

    Jensen, L; Jørgensen, L H; Bech, R D

    2016-01-01

    Muscle weakness is considered the pivotal sign of amyotrophic lateral sclerosis (ALS). Knowledge about the skeletal muscle degeneration/regeneration process and the myogenic potential is limited in ALS patients. Therefore, we investigate these processes in a time course perspective by analysing...

  12. Deep learning predictions of survival based on MRI in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van der Burgh, Hannelore K; Schmidt, Ruben; Westeneng, Henk-Jan; de Reus, Marcel A; van den Berg, Leonard H; van den Heuvel, Martijn P

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease, with large variation in survival between patients. Currently, it remains rather difficult to predict survival based on clinical parameters alone. Here, we set out to use clinical characteristics in combination with MRI data

  13. Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial

    NARCIS (Netherlands)

    Verstraete, Esther; Veldink, Jan H.; Huisman, Mark H. B.; Draak, Tim; Uijtendaal, Esther V.; van der Kooi, Anneke J.; Schelhaas, H. Jurgen; de Visser, Marianne; van der Tweel, Ingeborg; van den Berg, Leonard H.

    2012-01-01

    Objectives To determine the safety and efficacy of lithium for the treatment of amyotrophic lateral sclerosis (ALS) in a randomised, placebo controlled, double blind, sequential trial. Methods Between November 2008 and June 2011, 133 patients were randomised to receive lithium carbonate (target

  14. Amyotrophic lateral sclerosis presenting with orthopnea in a patient with COPD and obstructive sleep apnea

    Directory of Open Access Journals (Sweden)

    T.L.N. Swamy

    2011-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS, also known as motor neuron disease (MND is a relentlessly progressive neurological disorder causing peripheral muscular weakness and resultant respiratory failure. In this article, we report a case of ALS with chronic obstructive pulmonary disease (COPD and obstructive sleep apnea (OSA with orthopnea as initial symptoms.

  15. Increased IL-17, a Pathogenic Link between Hepatosplenic Schistosomiasis and Amyotrophic Lateral Sclerosis: A Hypothesis

    Directory of Open Access Journals (Sweden)

    Oswald Moling

    2014-01-01

    Full Text Available The immune system protects the organism from foreign invaders and foreign substances and is involved in physiological functions that range from tissue repair to neurocognition. However, an excessive or dysregulated immune response can cause immunopathology and disease. A 39-year-old man was affected by severe hepatosplenic schistosomiasis mansoni and by amyotrophic lateral sclerosis. One question that arose was, whether there was a relation between the parasitic and the neurodegenerative disease. IL-17, a proinflammatory cytokine, is produced mainly by T helper-17 CD4 cells, a recently discovered new lineage of effector CD4 T cells. Experimental mouse models of schistosomiasis have shown that IL-17 is a key player in the immunopathology of schistosomiasis. There are also reports that suggest that IL-17 might have an important role in the pathogenesis of amyotrophic lateral sclerosis. It is hypothesized that the factors that might have led to increased IL-17 in the hepatosplenic schistosomiasis mansoni might also have contributed to the development of amyotrophic lateral sclerosis in the described patient. A multitude of environmental factors, including infections, xenobiotic substances, intestinal microbiota, and vitamin D deficiency, that are able to induce a proinflammatory immune response polarization, might favor the development of amyotrophic lateral sclerosis in predisposed individuals.

  16. Acute deterioration of bulbar function after botulinum toxin treatment for sialorrhoea in amyotrophic lateral sclerosis.

    NARCIS (Netherlands)

    Meijer, J.W.; Kuijk, A.A. van; Geurts, A.C.H.; Schelhaas, H.J.; Zwarts, M.J.

    2008-01-01

    Transcutaneous botulinum toxin injection in the salivary glands was introduced in 2000 as a new treatment for sialorrhoea in amyotrophic lateral sclerosis (ALS). We describe an ALS patient who developed serious complications of botulinum toxin treatment for sialorrhoea, and we review the relevant

  17. Survival in patients with amyotrophic lateral sclerosis, treated with an array of antioxidants

    NARCIS (Netherlands)

    Vyth, A.; Timmer, J. G.; Bossuyt, P. M.; Louwerse, E. S.; de Jong, J. M.

    1996-01-01

    Between 1983 and 1988 we treated 36 patients with sporadic amyotrophic lateral sclerosis (ALS) by an array of antioxidants and added other drugs to the regimen whenever a patient reported deterioration. Our customary prescription sequence was N-acetylcysteine (NAC); vitamins C and E;

  18. Euthanasia and physician-assisted suicide among patients with amyotrophic lateral sclerosis in the Netherlands

    NARCIS (Netherlands)

    Veldink, Jan H.; Wokke, John H. J.; van der Wal, Gerrit; de Jong, J. M. B. Vianney; van den Berg, Leonard H.

    2002-01-01

    Amyotrophic lateral sclerosis (ALS) is a disease that causes progressive paralysis leading to respiratory failure. Patients with ALS may consider physician-assisted suicide. However, it is not known how many patients, if given the option, would actually decide to end their lives by

  19. Factor analysis of the Zarit Burden Interview in family caregivers of patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Oh, Juyeon; Kim, Jung A

    2018-02-01

    The Zarit Burden Interview has been used in many studies to assess caregiver burden in family caregivers of patients with amyotrophic lateral sclerosis, but the factor structure of the Zarit Burden Interview in the caregivers of amyotrophic lateral sclerosis patients is unknown. The aim of this study was to explore the factor structure of the Zarit Burden Interview in family caregivers of amyotrophic lateral sclerosis patients using exploratory factor analysis. The exploratory factor analysis was performed using generalized least squares with oblique rotation in a sample of 202 family caregivers. Three factors had an eigenvalue greater than 1 and accounted for 60.33% of the total variance. The three factors were named as follows: (factor 1) "Social restrictions" (items 2, 3, and 10-15); (factor 2) "Self-criticism" (items 20-21); and (factor 3) "Anger and frustration" (items 1, 4-6, 9, and 16-19). The correlation between factors 1 and 3 was much higher (r = 0.79) than that between factors 1 and 2 (r = 0.14) or factors 2 and 3 (r = 0.15). The findings of this study enriched our understanding of several meaningful dimensions of the caregiving burden in caregivers of an amyotrophic lateral sclerosis population and provided opportunities for future intervention.

  20. Prose memory impairment in amyotrophic lateral sclerosis patients is related to hippocampus volume

    NARCIS (Netherlands)

    Raaphorst, J.; van Tol, M. J.; de Visser, M.; van der Kooi, A. J.; Majoie, C. B.; van den Berg, L. H.; Schmand, B.; Veltman, D. J.

    2015-01-01

    Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study, brain atrophy in relation to memory function was investigated

  1. VAPB and C9orf72 mutations in 1 familial amyotrophic lateral sclerosis patient

    NARCIS (Netherlands)

    van Blitterswijk, Marka; van Es, Michael A.; Koppers, Max; van Rheenen, Wouter; Medic, Jelena; Schelhaas, Helenius J.; van der Kooi, Anneke J.; de Visser, Marianne; Veldink, Jan H.; van den Berg, Leonard H.

    2012-01-01

    Previously, we have reported amyotrophic lateral sclerosis (ALS) families with multiple mutations in major ALS-associated genes. These findings provided evidence for an oligogenic basis of ALS. In our present study, we screened a cohort of 755 sporadic ALS patients, 111 familial ALS patients (97

  2. Support needs of caregivers of patients with amyotrophic lateral sclerosis: A qualitative study

    NARCIS (Netherlands)

    de Wit, Jessica; Schröder, Carin D.; El Mecky, Julia; Beelen, Anita; van den Berg, Leonard H.; Visser-Meily, Johanna M. A.

    2018-01-01

    The aim of this study was to explore the support needs of Dutch informal caregivers of patients with amyotrophic lateral sclerosis (ALS). Individual semi-structured interviews were conducted with 21 caregivers of ALS patients. Audio-taped interviews were transcribed and data were analyzed

  3. Endothelin-1 is over-expressed in amyotrophic lateral sclerosis and induces motor neuron cell death

    NARCIS (Netherlands)

    Ranno, Eugenia; D'Antoni, Simona; Spatuzza, Michela; Berretta, Antonio; Laureanti, Floriana; Bonaccorso, Carmela M.; Pellitteri, Rosalia; Longone, Patrizia; Spalloni, Alida; Iyer, Anand M.; Aronica, Eleonora; Catania, Maria Vincenza

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons (MNs) and astrogliosis. Recent evidence suggests that factors secreted by activated astrocytes might contribute to degeneration of MNs. We focused on endothelin-1 (ET-1), a peptide

  4. Effects of the early diagnosis of amyotrophic lateral sclerosis on the patient: advantages.

    Science.gov (United States)

    Gelinas, D

    2000-03-01

    Advantages of early diagnoses in amyotrophic lateral sclerosis include validation of symptoms, avoidance of unnecessary procedures, enhanced preparation for disability and medical education. Most importantly, earlier in the course of the disease--while there is a greater motor neuron pool survival--diagnosis would enable earlier treatment intervention.

  5. Speech Movement Measures as Markers of Bulbar Disease in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Shellikeri, Sanjana; Green, Jordan R.; Kulkarni, Madhura; Rong, Panying; Martino, Rosemary; Zinman, Lorne; Yunusova, Yana

    2016-01-01

    Purpose: The goal of this study was to identify the effects of amyotrophic lateral sclerosis (ALS) on tongue and jaw control, both cross-sectionally and longitudinally. The data were examined in the context of their utility as a diagnostic marker of bulbar disease. Method: Tongue and jaw movements were recorded cross-sectionally (n = 33…

  6. Is There a Role for Exercise in the Management of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis?

    Science.gov (United States)

    Plowman, Emily K.

    2015-01-01

    Purpose: The role of exercise in the management of people with amyotrophic lateral sclerosis (PALS) is controversial and currently unclear. The purpose of this review article is to review literature examining the impact of limb, respiratory, and oral motor exercise on function, disease progression, and survival in PALS and the transgenic ALS…

  7. Methods of Communication at End of Life for the Person with Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Brownlee, Alisa; Bruening, Lisa M.

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in loss of most motor functions by the time of death. Most persons with ALS experience a dysarthria that eventually renders oral/vocal communication unintelligible. This article reviews the communication needs of persons with ALS and the range of communication…

  8. Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Radunovic, Aleksandar; Annane, Djillali; Rafiq, Muhammad K; Brassington, Ruth; Mustfa, Naveed

    2017-10-06

    Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal neurodegenerative disease. Neuromuscular respiratory failure is the most common cause of death, which usually occurs within two to five years of the disease onset. Supporting respiratory function with mechanical ventilation may improve survival and quality of life. This is the second update of a review first published in 2009. To assess the effects of mechanical ventilation (tracheostomy-assisted ventilation and non-invasive ventilation (NIV)) on survival, functional measures of disease progression, and quality of life in ALS, and to evaluate adverse events related to the intervention. We searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, and AMED on 30 January 2017. We also searched two clinical trials registries for ongoing studies. Randomised controlled trials (RCTs) and quasi-RCTs involving non-invasive or tracheostomy-assisted ventilation in participants with a clinical diagnosis of ALS, independent of the reported outcomes. We included comparisons with no intervention or the best standard care. For the original review, four review authors independently selected studies for assessment. Two review authors reviewed searches for this update. All review authors independently extracted data from the full text of selected studies and assessed the risk of bias in studies that met the inclusion criteria. We attempted to obtain missing data where possible. We planned to collect adverse event data from the included studies. For the original Cochrane Review, the review authors identified two RCTs involving 54 participants with ALS receiving NIV. There were no new RCTs or quasi-RCTs at the first update. One new RCT was identified in the second update but was excluded for the reasons outlined below.Incomplete data were available for one published study comparing early and late initiation of

  9. Immunohistological alterations in muscle of patients with amyotrophic lateral sclerosis: mononuclear cell phenotypes and expression of MHC products

    NARCIS (Netherlands)

    Troost, D.; Das, P. K.; van den Oord, J. J.; Louwerse, E. S.

    1992-01-01

    Muscle biopsy specimens from 15 autopsied patients with the isolated form of amyotrophic lateral sclerosis were examined by routine histological and immunocytochemical methods using a panel of monoclonal antibodies directed against differentiation and activation markers of immunocompetent cells. In

  10. Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology.

    Science.gov (United States)

    Kassubek, Jan; Müller, Hans-Peter; Del Tredici, Kelly; Brettschneider, Johannes; Pinkhardt, Elmar H; Lulé, Dorothée; Böhm, Sarah; Braak, Heiko; Ludolph, Albert C

    2014-06-01

    Diffusion tensor imaging can identify amyotrophic lateral sclerosis-associated patterns of brain alterations at the group level. Recently, a neuropathological staging system for amyotrophic lateral sclerosis has shown that amyotrophic lateral sclerosis may disseminate in a sequential regional pattern during four disease stages. The objective of the present study was to apply a new methodological diffusion tensor imaging-based approach to automatically analyse in vivo the fibre tracts that are prone to be involved at each neuropathological stage of amyotrophic lateral sclerosis. Two data samples, consisting of 130 diffusion tensor imaging data sets acquired at 1.5 T from 78 patients with amyotrophic lateral sclerosis and 52 control subjects; and 55 diffusion-tensor imaging data sets at 3.0 T from 33 patients with amyotrophic lateral sclerosis and 22 control subjects, were analysed by a tract of interest-based fibre tracking approach to analyse five tracts that become involved during the course of amyotrophic lateral sclerosis: the corticospinal tract (stage 1); the corticorubral and the corticopontine tracts (stage 2); the corticostriatal pathway (stage 3); the proximal portion of the perforant path (stage 4); and two reference pathways. The statistical analyses of tracts of interest showed differences between patients with amyotrophic lateral sclerosis and control subjects for all tracts. The significance level of the comparisons at the group level was lower, the higher the disease stage with corresponding involved fibre tracts. Both the clinical phenotype as assessed by the amyotrophic lateral sclerosis functional rating scale-revised and disease duration correlated significantly with the resulting staging scheme. In summary, the tract of interest-based technique allowed for individual analysis of predefined tract structures, thus making it possible to image in vivo the disease stages in amyotrophic lateral sclerosis. This approach can be used not only for

  11. Comment on the article titled "Increased Incidence of Amyotrophic Lateral Sclerosis in Polymyositis: A Nationwide Cohort Study".

    Science.gov (United States)

    Parperis, Konstantinos

    2017-10-03

    With interest, I read the recent article in Arthritis Care and Research titled "Increased Incidence of Amyotrophic Lateral Sclerosis in Polymyositis: A Nationwide Cohort Study" (1). Tseng at al (1) conducted a retrospective cohort study in Taiwan, exploring a link between amyotrophic lateral sclerosis (ALS) and polymyositis (PM). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. De novo FUS P525L mutation in Juvenile amyotrophic lateral sclerosis with dysphonia and diplopia.

    Science.gov (United States)

    Leblond, Claire S; Webber, Alina; Gan-Or, Ziv; Moore, Fraser; Dagher, Alain; Dion, Patrick A; Rouleau, Guy A

    2016-04-01

    Juvenile amyotrophic lateral sclerosis (jALS) is characterized by progressive upper and lower motor neuron degeneration leading to facial muscle spasticity, spastic dysarthria, and spastic gait with an early onset (before 25 years old). Unlike adult-onset amyotrophic lateral sclerosis (ALS), patients with jALS tend to have slower progression of motor neuron disease and prolonged survival to a normal life expectancy. Mutations in FUS gene have been reported in jALS,(1) including p.P525L mutation that has been consistently associated with early onset and aggressive presentation.(2) Here, we report a patient carrying p.P525L FUS mutation and experiencing an aggressive course of ALS presenting with dysphonia and diplopia.

  13. Information-seeking Behavior and Information Needs in Patients With Amyotrophic Lateral Sclerosis: Analyzing an Online Patient Community.

    Science.gov (United States)

    Oh, Juyeon; Kim, Jung A

    2017-07-01

    A few studies have examined the specific informational needs of the population with amyotrophic lateral sclerosis. The aims of this study were to describe the information-seeking behavior and information needs of patients with amyotrophic lateral sclerosis and their families in Korea by analyzing messages from an online patient community. A total of 1047 messages from the question and answer forum of the "Lou Gehrig's Disease Network" (http://cafe.daum.net/alsfree) from January 2010 to September 2015 were collected. The word frequency, main questions, and asker of the messages were analyzed and coded. Terms such as "hospital," "mother," "father," "gastrostomy," and "ALS" were most frequently identified. The most commonly mentioned main topic was about disease-specific information, while the most frequent subcategory was symptoms or management of symptoms. Other prominent categories concerned information about treatment, rehabilitation, and the medical system. The people who wrote the questions were mostly the son/daughter of patients with amyotrophic lateral sclerosis. Patients with amyotrophic lateral sclerosis and their family members commonly obtained information by posting their inquiries online and have a variety of questions regarding amyotrophic lateral sclerosis in this study. The findings of this study can be used as a base of information for developing educational programs and resources for patients with amyotrophic lateral sclerosis and their families.

  14. Amyotrophic Lateral Sclerosis Presenting Respiratory Failure as the Sole Initial Manifestation

    Directory of Open Access Journals (Sweden)

    Fuyuki Tateno

    2014-08-01

    Full Text Available It is rare that amyotrophic lateral sclerosis (ALS presents with respiratory failure as the sole initial manifestation. A 72-year-old man with mild chronic obstructive pulmonary disease developed exertional dyspnea for 13 months. He then progressed to limb weakness that led to the diagnosis of ALS. Although rare, ALS can present with respiratory failure as the sole initial manifestation more than 1 year prior to limb weakness.

  15. Association Between Blood Lead and the Risk of Amyotrophic Lateral Sclerosis

    OpenAIRE

    Fang, Fang; Kwee, Lydia C.; Allen, Kelli D.; Umbach, David M.; Ye, Weimin; Watson, Mary; Keller, Jean; Oddone, Eugene Z.; Sandler, Dale P.; Schmidt, Silke; Kamel, Freya

    2010-01-01

    The authors conducted a 2003–2007 case-control study including 184 cases and 194 controls to examine the association between blood lead and the risk of amyotrophic lateral sclerosis (ALS) among US veterans and to explore the influence on this association of bone turnover and genetic factors related to lead toxicokinetics. Blood lead, plasma biomarkers of bone formation (procollagen type 1 amino-terminal peptide (PINP)) and resorption (C-terminal telopeptides of type 1 collagen (CTX)), and the...

  16. Magnetic resonance findings in amyotrophic lateral sclerosis using a spin echo magnetization transfer sequence: preliminary report

    Directory of Open Access Journals (Sweden)

    ROCHA ANTÔNIO JOSÉ DA

    1999-01-01

    Full Text Available We present the magnetic resonance (MR findings of five patients with amyotrophic lateral sclerosis (ALS using a spin-echo sequence with an additional magnetization transfer (MT pulse on T1-weighted images (T1 SE/MT. These findings were absent in the control group and consisted of hyperintensity of the corticospinal tract. Moreover we discuss the principles and the use of this fast but simple MR technique in the diagnosis of ALS

  17. Diffusion tensor imaging and voxel based morphometry study in amyotrophic lateral sclerosis: relationships with motor disability

    OpenAIRE

    Thivard, Lionel; Pradat, Pierre‐François; Lehéricy, Stéphane; Lacomblez, Lucette; Dormont, Didier; Chiras, Jacques; Benali, Habib; Meininger, Vincent

    2007-01-01

    International audience; The aim of this study was to investigate the extent of cortical and subcortical lesions in amyotrophic lateral sclerosis (ALS) using, in combination, voxel based diffusion tensor imaging (DTI) and voxel based morphometry (VBM). We included 15 patients with definite or probable ALS and 25 healthy volunteers. Patients were assessed using the revised ALS Functional Rating Scale (ALSFRS-R). In patients, reduced fractional anisotropy was found in bilateral corticospinal tra...

  18. An Overview of Potential Targets for Treating Amyotrophic Lateral Sclerosis and Huntington’s Disease

    Directory of Open Access Journals (Sweden)

    Caroline Zocatelli de Paula

    2015-01-01

    Full Text Available Neurodegenerative diseases affect millions of people worldwide. Progressive damage or loss of neurons, neurodegeneration, has severe consequences on the mental and physical health of a patient. Despite all efforts by scientific community, there is currently no cure or manner to slow degeneration progression. We review some treatments that attempt to prevent the progress of some of major neurodegenerative diseases: Amyotrophic Lateral Sclerosis and Huntington’s disease.

  19. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis.

    Science.gov (United States)

    Johnson, Janel O; Pioro, Erik P; Boehringer, Ashley; Chia, Ruth; Feit, Howard; Renton, Alan E; Pliner, Hannah A; Abramzon, Yevgeniya; Marangi, Giuseppe; Winborn, Brett J; Gibbs, J Raphael; Nalls, Michael A; Morgan, Sarah; Shoai, Maryam; Hardy, John; Pittman, Alan; Orrell, Richard W; Malaspina, Andrea; Sidle, Katie C; Fratta, Pietro; Harms, Matthew B; Baloh, Robert H; Pestronk, Alan; Weihl, Conrad C; Rogaeva, Ekaterina; Zinman, Lorne; Drory, Vivian E; Borghero, Giuseppe; Mora, Gabriele; Calvo, Andrea; Rothstein, Jeffrey D; Drepper, Carsten; Sendtner, Michael; Singleton, Andrew B; Taylor, J Paul; Cookson, Mark R; Restagno, Gabriella; Sabatelli, Mario; Bowser, Robert; Chiò, Adriano; Traynor, Bryan J

    2014-05-01

    MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.

  20. Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems.

    Directory of Open Access Journals (Sweden)

    Mireia Herrando-Grabulosa

    Full Text Available Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology, we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis.

  1. Awake fi beroptic intubation of a patient with amyotrophic lateral sclerosis: case report

    Directory of Open Access Journals (Sweden)

    Elif Bakı

    2012-12-01

    Full Text Available Amyotrophic Lateral Sclerosis is a rapidly progressive disease from the fi fth to sixth decades of life causing degeneration and death of the upper and lower motor neurons and no effective treatment. The diagnosis isdependent on the clinical presentation and consistent electrodiagnostic studies. Progressive denervation affects the muscles, causing muscular weakness and atrophy, when the ventilation muscles are affected deathdue to respiratory failure occurs within a few years. We present the case of a 54 years old, 180 cm height and 94 kg weight male patient with amyotrophic lateral sclerosis who underwent surgical treatment of thyroidcancer. Fiberoptic intubation was orally performed providing spontaneus breathing. Propofol was applied after passing vocal cords. Anesthesia was maintained with sevofl orane (%2 and a mixture of oxygen and airunder volume controlled ventilation. Rocuronium was used 20 mg at the beginning of the surgery. At the end of surgery, he wasn’t extubated and transferred to anesthesia intensive care unit. He was extubated after tenhours and he was awaked perfectly. The patient was discharged from intensive care unit after 24 hours and from hospital after ten days. We reported that amyotrophic lateral sclerosis patient with limited mouth opening who underwent thyroid surgery, using awake intubation.

  2. Supportive care needs of patients with amyotrophic lateral sclerosis/motor neuron disease and their caregivers: A scoping review.

    Science.gov (United States)

    Oh, Juyeon; Kim, Jung A

    2017-12-01

    To identify the supportive care needs of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, categorise and summarise them into a Supportive Care Needs Framework and identify gaps in literature. Little is known about the supportive care needs of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, and this subject has not previously been systemically reviewed. Scoping review. We conducted a scoping review from the MEDLINE, EMBASE, CINAHL and Cochrane databases for the period January 2000-July 2016, using the following inclusion criteria: (i) written in English only, (ii) published in peer-reviewed journals, (iii) at least part of the research considered the supportive care needs perspective of amyotrophic lateral sclerosis/motor neuron disease patients or their caregivers and (iv) the population sample included patients of amyotrophic lateral sclerosis/motor neuron disease or their caregivers. Thirty-seven articles were included. Our review shows that amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers' supportive care needs were mentioned across all seven domains of the Supportive Care Needs Framework. Most common were practical needs (n = 24), followed by Informational needs (n = 19), Social needs (n = 18), Psychological needs (n = 16), Physical needs (n = 15), Emotional needs (n = 13) and Spiritual needs (n = 8). From the perspectives of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, there is a significant need for more practical, social, informational, psychological, physical, emotional and spiritual support. The Supportive Care Needs Framework has potential utility in the development of patient-centred support services or healthcare policies and serves as an important base for further studies; especially, specific examples of each supportive care needs domain can guide in clinical settings when healthcare professionals

  3. Application of botulinum toxin to treat sialorrhea in amyotrophic lateral sclerosis patients: a literature review.

    Science.gov (United States)

    Oliveira, Ademar Francisco de; Silva, Gêssyca Adryene de Menezes; Almeida, Débora Milenna Xavier

    2016-01-01

    Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease characterized by the degeneration of motor neurons, which are the central nervous system cells that control voluntary muscle movements. The excessive salivation (sialorrhea) is present in approximately 50% of amyotrophic lateral sclerosis cases. Thus, some alternative therapeutic methods are sought, such as anticholinergic drugs and surgery. Recently the use of botulinum toxin applied at a midpoint of the salivary glands, often guided by ultrasound, have demonstrated positive results. The objective was to review the literature to demonstrate an alternative method to treatments of sialorrhea in patients with amyotrophic lateral sclerosis. In recent studies, the efficacy of botulinum toxin is confirmed, although new applications are required. Since the side effects are negligible, this is an alternative to treat amyotrophic lateral sclerosis, and other patients with diseases that present sialorrhea. RESUMO Esclerose lateral amiotrófica é uma doença neurodegenerativa progressiva e fatal, caracterizada pela degeneração dos neurônios motores, as células do sistema nervoso central que controlam os movimentos voluntários dos músculos. A salivação excessiva (sialorreia) está presente em cerca de 50% dos casos de esclerose lateral amiotrófica. Dessa forma, surgem medidas terapêuticas alternativas como drogas anticolinérgicas e cirurgia, e recentemente, o uso da toxina botulínica, aplicada em um ponto central das glândulas salivares, muitas vezes guiado por ultrassonografia, demostrou resultados positivos. Objetivou-se revisar a literatura no intuito de demonstrar um método alternativo aos tratamentos de sialorreia em pacientes com esclerose lateral amiotrófica. Em estudos recentes, a eficácia do tratamento com toxina botulínica foi confirmada e, mesmo requerendo novas aplicações, os efeitos colaterais são ínfimos. Ela surge então como alternativa não só ao

  4. Genetic analysis of matrin 3 gene in French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral sclerosis patients.

    Science.gov (United States)

    Millecamps, Stéphanie; De Septenville, Anne; Teyssou, Elisa; Daniau, Mailys; Camuzat, Agnès; Albert, Mélanie; LeGuern, Eric; Galimberti, Daniela; Brice, Alexis; Marie, Yannick; Le Ber, Isabelle

    2014-12-01

    Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are adult-onset neurodegenerative diseases with overlapping clinical characteristics. They share common genetic causes and pathologic hallmarks such as TDP-43 neuronal accumulations. Recently, exome analysis identified mutations in matrin 3 (MATR3) gene in patients with familial ALS, suggesting a role for this gene in the pathogenesis of the disease. MATR3 is a nuclear matrix protein with DNA and RNA binding domains that interacts with TDP-43. To confirm the contribution of MATR3 to ALS, we studied a French cohort of 153 familial ALS or ALS/FTLD patients, without finding any variant. We conclude that mutations in MATR3 are rare in French familial ALS and ALS with FTLD patients. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. A PET/CT approach to spinal cord metabolism in amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Marini, Cecilia [CNR Institute of Bioimages and Molecular Physiology, Milan, Section of Genoa (Italy); University of Genoa, Nuclear Medicine, IRCCS San Martino IST, and Depth of Health Science, Genoa (Italy); IRCCS AOU San Martino-IST, CNR Institute of Bioimages and Molecular Physiology, Section of Genoa, C/o Nuclear Medicine, Genoa (Italy); Cistaro, Angelina; Fania, Piercarlo [Positron Emission Tomography Centre IRMET, Affidea, Turin (Italy); Campi, Cristina; Perasso, Annalisa; Massone, Anna Maria [SPIN Institute, CNR, Genoa (Italy); Calvo, Andrea; Moglia, Cristina; Canosa, Antonio; Cammarosano, Stefania; Chio, Adriano [University of Turin, ALS Center, ' ' Rita Levi Montalcini' ' Department of Neuroscience, Turin (Italy); AUO Citta della Salute e della Scienza, Turin (Italy); Caponnetto, Claudia; Nobili, Flavio Mariano; Novi, Giovanni; Scialo, Carlo; Mancardi, Gianluigi [IRCCS San Martino IST, Department of Neuroscience, Genoa (Italy); DINOGMI University of Genoa, Genoa (Italy); Beltrametti, Mauro C. [University of Genoa, Department of Mathematics (DIMA), Genoa (Italy); Buschiazzo, Ambra; Pomposelli, Elena; Morbelli, Silvia; Sambuceti, Gianmario [University of Genoa, Nuclear Medicine, IRCCS San Martino IST, and Depth of Health Science, Genoa (Italy); Bagnara, Maria Claudia [IRCCS AOU San Martino-IST, Medical Physics unit, Genoa (Italy); Bruzzi, Paolo [IRCCS AOU San Martino-IST, Statistics and Epidemiology Unit, Genoa (Italy); Piana, Michele [SPIN Institute, CNR, Genoa (Italy); University of Genoa, Department of Mathematics (DIMA), Genoa (Italy)

    2016-10-15

    In amyotrophic lateral sclerosis, functional alterations within the brain have been intensively assessed, while progression of lower motor neuron damage has scarcely been defined. The aim of the present study was to develop a computational method to systematically evaluate spinal cord metabolism as a tool to monitor disease mechanisms. A new computational three-dimensional method to extract the spinal cord from {sup 18}F-FDG PET/CT images was evaluated in 30 patients with spinal onset amyotrophic lateral sclerosis and 30 controls. The algorithm identified the skeleton on the CT images by using an extension of the Hough transform and then extracted the spinal canal and the spinal cord. In these regions, {sup 18}F-FDG standardized uptake values were measured to estimate the metabolic activity of the spinal canal and cord. Measurements were performed in the cervical and dorsal spine and normalized to the corresponding value in the liver. Uptake of {sup 18}F-FDG in the spinal cord was significantly higher in patients than in controls (p < 0.05). By contrast, no significant differences were observed in spinal cord and spinal canal volumes between the two groups. {sup 18}F-FDG uptake was completely independent of age, gender, degree of functional impairment, disease duration and riluzole treatment. Kaplan-Meier analysis showed a higher mortality rate in patients with standardized uptake values above the fifth decile at the 3-year follow-up evaluation (log-rank test, p < 0.01). The independence of this value was confirmed by multivariate Cox analysis. Our computational three-dimensional method enabled the evaluation of spinal cord metabolism and volume and might represent a potential new window onto the pathophysiology of amyotrophic lateral sclerosis. (orig.)

  6. Current issues in the respiratory care of patients with amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Marco Orsini

    2015-10-01

    Full Text Available Amyotrophic lateral sclerosis is a progressive neuromuscular disease, resulting in respiratory muscle weakness, reduced pulmonary volumes, ineffective cough, secretion retention, and respiratory failure. Measures as vital capacity, maximal inspiratory and expiratory pressures, sniff nasal inspiratory pressure, cough peak flow and pulse oximetry are recommended to monitor the respiratory function. The patients should be followed up by a multidisciplinary team, focused in improving the quality of life and deal with the respiratory symptoms. The respiratory care approach includes airway clearance techniques, mechanically assisted cough and noninvasive mechanical ventilation. Vaccination and respiratory pharmacological support are also recommended. To date, there is no enough evidence supporting the inspiratory muscle training and diaphragmatic pacing.

  7. [An early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development].

    Science.gov (United States)

    Abe, Koji

    2018-03-28

    The present review focuses an early history of Japanese amyotrophic lateral sclerosis (ALS)-related diseases and the current development. In relation to foreign previous reports, five topics are introduced and discussed on ALS with dementia, ALS/Parkinsonism dementia complex (ALS/PDC), familial ALS (FALS), spinal bulbar muscular atrophy (SBMA), and multisystem involvement especially in cerebellar system of ALS including ALS/SCA (spinocerebellar ataxia) crossroad mutation Asidan. This review found the great contribution of Japanese reports on the above five topics, and confirmed the great development of ALS-related diseases over the past 120 years.

  8. Pyramidal tract deficits and polyneuropathy in hyperthyroidism, Combination clinically mimicking amyotrophic lateral sclerosis.

    Science.gov (United States)

    Fisher, M; Mateer, J E; Ullrich, I; Gutrecht, J A

    1985-06-01

    Generalized weakness, intermittent dysphagia, and a 40-pound weight loss developed in an elderly man over a six-month period. Examination revealed weakness, atrophy and fasciculations of extremity musculature, pseudobulbar speech, hyperactive upper extremity reflexes, and extensor toe signs without sensory loss. Results of electrodiagnostic studies were consistent with an axonal polyneuropathy. Endocrinologic results were compatible with hyperthyroidism. Radioiodine therapy resulted in resolution of clinical neurologic symptoms and signs within seven months. This case illustrates a previously undescribed concurrence of hyperthyroid associated polyneuropathy and pyramidal tract dysfunction that led to an initial clinical diagnosis of amyotrophic lateral sclerosis.

  9. Intraneuronal aluminum accumulation in amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam

    International Nuclear Information System (INIS)

    Perl, D.P.; Gajdusek, D.C.; Garruto, R.M.; Yanagihara, R.T.; Gibbs, C.J.

    1982-01-01

    Scanning electron microscopy with energy-dispersive x-ray spectrometry was used to analyze the elemental content of neurofibrillary tangle (NFT)-bearing and NFT-free neurons within the Sommer's sector (H1 region) of the hippocampus in Guamanian Chamorros with amyotrophic lateral sclerosis and parkinsonism-dementia and in neurologically normal controls. Preliminary data indicate prominent accumulation of aluminum within the nuclear region and perikaryal cytoplasm of NFT-bearing hippocampal neurons, regardless of the underlying neurological diagnosis. These findings further extend the association between intraneuronal aluminum and NFT formation and support the hypothesis that environmental factors are related to the neurodegenerative changes seen in the Chamorro population

  10. Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Statland, Jeffrey M; Barohn, Richard J; McVey, April L; Katz, Jonathan S; Dimachkie, Mazen M

    2015-11-01

    When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Quantification of brain metabolites in amyotrophic lateral sclerosis by localized proton magnetic resonance spectroscopy

    DEFF Research Database (Denmark)

    Gredal, O; Rosenbaum, S; Topp, S

    1997-01-01

    20-mm3 voxel placed in the motor cortex and in the cerebellum from seven patients with clinically probable or definite amyotrophic lateral sclerosis (ALS) according to the El Escorial criteria, from three patients with suspected ALS (progressive muscular atrophy), and from eight normal control...... subjects. We estimated the concentrations of the metabolites using the water signal as an internal standard. The concentrations of Cho and Cr/PCr in both brain regions, as well as the concentration of NAA in the cerebellum, were unaltered in the MND patients compared with the controls. Only MND patients...

  12. A Novel Missense Mutation of the DDHD1 Gene Associated with Juvenile Amyotrophic Lateral Sclerosis

    OpenAIRE

    Wu, Chujun; Fan, Dongsheng

    2016-01-01

    Background: Juvenile amyotrophic lateral sclerosis (jALS) is a rare form of ALS with an onset age of less than 25 years and is frequently thought to be genetic in origin. DDHD1 gene mutations have been reported to be associated with the SPG28 subtype of autosomal recessive HSP but have never been reported in jALS patients. Methods: Gene screens for the causative genes of ALS, HSP and CMT using next-generation sequencing (NGS) technologies were performed on a jALS patient. Sanger sequencing wa...

  13. Cronobacter sakazakii DNA Detection in Cerebrospinal Fluid of a Patient with Amyotrophic Lateral Sclerosis Mimic Syndrome

    Directory of Open Access Journals (Sweden)

    Marianna Piombo

    2015-12-01

    Full Text Available A 45-year-old male noticed progressive weakness of the right lower limb with gait disturbance. Over the following months, motor deficits worsened, spreading to the right upper limb. Electromyography showed active denervation in the upper and lower limb muscles. A diagnosis of amyotrophic lateral sclerosis (ALS was made. About 2 years after symptom onset, gradual improvement occurred. Cerebrospinal fluid analysis performed about 3 years after the beginning of symptoms identified Cronobacter sakazakii. Since no other possible causes were identified, we suggest that an almost completely reversible ALS-like syndrome had been triggered by Cronobacter infection in our immunocompetent patient.

  14. Higher risk of complications in odynophagia-associated dysphagia in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Karen Fontes Luchesi

    2014-03-01

    Full Text Available Objective This investigation aimed to identify associated factors with dysphagia severity in amyotrophic lateral sclerosis (ALS. Method We performed a cross-sectional study of 49 patients with ALS. All patients underwent fiberoptic endoscopy evaluation of swallowing and answered a verbal questionnaire about swallowing complaints. The patients were divided into groups according to dysphagia severity. Results Among the factors analyzed, only odynophagia was associated with moderate or severe dysphagia. Conclusion Odynophagia was associated with moderate and severe dysphagia in ALS and suggests a high risk of pulmonary and nutritional complications.

  15. Distribution of Arsenic, Manganese, and Selenium in the Human Brain in Chronic Renal Insufficiency, Parkinsons Disease and Amyotrophic Lateral Sclerosis

    DEFF Research Database (Denmark)

    Larsen, N. A.; Pakkenberg, H.; Damsgaard, Else

    1981-01-01

    The concentrations of arsenic, manganese and selenium/g wet tissue weight were determined in samples from 24 areas of the human brain from 3 patients with chronic renal insufficiency, 2 with Parkinson's disease and 1 with amyotrophic lateral sclerosis. The concentrations of the 3 elements were...... determined for each sample by neutron activation analysis with radiochemical separation. Overall arsenic concentrations were about 2.5 times higher in patients with chronic renal failure than in controls, and lower than normal in the patients with Parkinson's disease and amyotrophic lateral sclerosis...

  16. The Cyanobacteria Derived Toxin Beta-N-Methylamino-L-Alanine and Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Elijah W. Stommel

    2010-12-01

    Full Text Available There is mounting evidence to suggest that environmental factors play a major role in the development of neurodegenerative diseases like ALS (Amyotrophic Lateral Sclerosis. The non-protein amino acid beta-N-methylamino-L-alanine (BMAA was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC in Guam, and has been implicated as a potential environmental factor in ALS, Alzheimer’s disease, and other neurodegenerative diseases. BMAA has a number of toxic effects on motor neurons including direct agonist action on NMDA and AMPA receptors, induction of oxidative stress, and depletion of glutathione. As a non-protein amino acid, there is also the strong possibility that BMAA could cause intraneuronal protein misfolding, the hallmark of neurodegeneration. While an animal model for BMAA-induced ALS is lacking, there is substantial evidence to support a link between this toxin and ALS. The ramifications of discovering an environmental trigger for ALS are enormous. In this article, we discuss the history, ecology, pharmacology and clinical ramifications of this ubiquitous, cyanobacteria-derived toxin.

  17. A Bibliometric Assessment of Global Ice Bucket Challenge (Amyotrophic Lateral Sclerosis) Research.

    Science.gov (United States)

    Ram, Shri

    2016-10-01

    This study is a quantitative and qualitative assessment of the global research trends on amyotrophic lateral sclerosis (ALS) (popularly known as Ice Bucket Challenge), through related literatures retrieved from SCOPUS multidisciplinary database for the period 1974-2013. This study is aimed at analyzing the literature on ALS in terms of document type, language, annual growth, productive country, journal, authors, subject, and most cited articles. The bibliographic data for this study was retrieved from the SCOPUS database using keywords 'amyotrophic lateral sclerosis', 'motor neurone disease', 'Charcot disease', 'Lou Gehrig's disease', 'Ice Bucket Challenge' available in title, abstract, and keyword fields of Scopus database from 1974 to 2013. The literature analysis included 21,750 articles during the period from 1974 to 2013 in different areas of ALS. USA was the most productive country in terms of literature produced, while Neurology was the most productive journal. An intensive awareness created by 'Ice Bucket Challenge' has attracted masses, and an intensive growth of literature is pertinent on ALS. The results of this study are expressed in terms of growth of literature, output of individual countries, and authors, and will be helpful in collaborative research in future.

  18. Correlation between functional independence and quality of life of patients with amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Nathalia Priscilla Oliveira Silva

    2014-12-01

    Full Text Available Functional independence and quality of life are impacted by amyotrophic lateral sclerosis (ALS, a degenerative and progressive disease. The aim of this study was to investigate the functional independence and quality of life of patients with ALS in the municipality of Natal, Rio Grande do Norte state, Brazil. This is a cross-sectional observational study conducted with 24 patients. The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40/BR and the Functional Independence Measure (FIM were used as evaluation instruments. The data were analyzed through the Spearman’s correlation and Mann-Whitney tests. The individuals investigated presented modified functional dependence in the FIM, with mean of 64.9±20.5, and alteration in all areas of the ALSAQ-40/ BR. There was significant inverse correlation between FIM and the ALSAQ-40/BR areas of “Mobility” (p<0.01, “Activities of Daily Living (DLAs” (p<0.01, “Eating ability” (p=0.02, and “Communication” (p<0.01, but not in the domain of “Emotional Aspect”. Despite the reduced sample, all patients presented reduction in functional independence and quality of life. The use of these instruments may be a tool to assist the elaboration of intervention plans and interdisciplinary treatment, contributing to retard functional dependence and improve the quality of life of these patients.

  19. Spatial Elucidation of Spinal Cord Lipid- and Metabolite- Regulations in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Hanrieder, Jörg; Ewing, Andrew G.

    2014-06-01

    Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressing disease of the central nervous system that is characterized by motor neuron degeneration in the brain stem and the spinal cord. We employed time of flight secondary ion mass spectrometry (ToF-SIMS) to profile spatial lipid- and metabolite- regulations in post mortem human spinal cord tissue from ALS patients to investigate chemical markers of ALS pathogenesis. ToF-SIMS scans and multivariate analysis of image and spectral data were performed on thoracic human spinal cord sections. Multivariate statistics of the image data allowed delineation of anatomical regions of interest based on their chemical identity. Spectral data extracted from these regions were compared using two different approaches for multivariate statistics, for investigating ALS related lipid and metabolite changes. The results show a significant decrease for cholesterol, triglycerides, and vitamin E in the ventral horn of ALS samples, which is presumably a consequence of motor neuron degeneration. Conversely, the biogenic mediator lipid lysophosphatidylcholine and its fragments were increased in ALS ventral spinal cord, pointing towards neuroinflammatory mechanisms associated with neuronal cell death. ToF-SIMS imaging is a promising approach for chemical histology and pathology for investigating the subcellular mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis.

  20. Nutritional assessment of amyotrophic lateral sclerosis in routine practice: value of weighing and bioelectrical impedance analysis.

    Science.gov (United States)

    Roubeau, Vincent; Blasco, Hélène; Maillot, François; Corcia, Philippe; Praline, Julien

    2015-04-01

    We evaluated clinical and bioelectrical impedance (BIA) parameters at the time of diagnosis and during follow-up and associated these parameters with survival in amyotrophic lateral sclerosis (ALS) patients. One hundred seventeen patients were enrolled and were evaluated prospectively every 3 months. All patients underwent at least 1 BIA-based assessment, and 73 underwent at least 2 assessments. Data regarding the site of onset, age at onset, weight, body mass index (BMI), amyotrophic lateral sclerosis functional rating scale score (ALSFRS), fat-free mass (FFM), fat mass (FM), and phase angle (PA) were collected. At the time of diagnosis, weight loss exceeding 5% of the premorbid weight and low PA were poor prognostic factors. During follow-up, a decrease of PA and FFM were associated with shorter survival, regardless of weight loss. These results confirm that BIA is useful to identify poor prognostic factors at the time of diagnosis and during follow-up and thus could be used to monitor patients during follow-up. Early identification of poor prognostic factors enables nutritional management and might improve patient survival. © 2014 Wiley Periodicals, Inc.

  1. Cross-diagnostic validity of the SF-36 physical functioning scale in patients with stroke, multiple sclerosis and amyotrophic lateral sclerosis: a study using Rasch analysis

    NARCIS (Netherlands)

    Dallmeijer, Annet J.; de Groot, Vincent; Roorda, Leo D.; Schepers, Vera P. M.; Lindeman, Eline; van den Berg, Leonard H.; Beelen, Anita; Dekker, Joost

    2007-01-01

    The aim of this study was to investigate unidimensionality and differential item functioning of the SF-36 physical functioning scale (PF10) in patients with various neurological disorders. Patients: Patients post-stroke (n = 198), with multiple sclerosis (n = 151) and amyotrophic lateral sclerosis

  2. Novel FUS deletion in a patient with juvenile amyotrophic lateral sclerosis.

    Science.gov (United States)

    Belzil, Veronique V; Langlais, Jean-Sébastien; Daoud, Hussein; Dion, Patrick A; Brais, Bernard; Rouleau, Guy A

    2012-05-01

    Juvenile amyotrophic lateral sclerosis (JALS) refers to a form of amyotrophic lateral sclerosis (ALS) in which a progressive upper and lower motor neuron degeneration begins before 25 years of age. It is generally associated with slow disease progression. During the past decade, a number of genes have been reported to cause JALS. Mutations in the ALSIN gene cause JALS type 2 (ALS2) as well as juvenile primary lateral sclerosis and infantile-onset ascending spastic paralysis. Mutations in the SETX gene can also sometimes lead to JALS. Conversely, mutations in SOD1, TARDBP, and FUS typically cause pure ALS, with adult onset between 46 and 56 years of age and usually rapid progression over 3 to 5 years. Recently, a few mutations in FUS have been associated with juvenile-onset of ALS characterized by a very rapid progression. To investigate the genetics of a patient with juvenile-onset ALS. We sequenced all the coding exons of SOD1, TARDBP, and FUS in a 19-year-old patient experiencing rapid degeneration of upper and lower motor neurons. A novel 1-base pair deletion was detected in exon 14 of the FUS gene, leading to a frameshift and the integration of 33 new amino acids. The variant p.R495QfsX527 is located in the highly conserved, extreme C terminal of the FUS protein, where most of the mutations in FUS have been identified. The variant was also identified in the unaffected 47-year-old mother of the patient, who remains asymptomatic. Our finding, along with other research, further confirms that FUS mutations can lead to an early-onset malignant form of ALS. In addition, our data lend additional support to the notion that disruption of the conserved C terminal of FUS is critical for developing ALS.

  3. Spread Direction and Prognostic Factors in Limb-Onset Sporadic Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Hu, Fangfang; Jin, Jiaoting; Jia, Rui; Xiang, Li; Qi, Huaguang; Chen, Xin; Dang, Jingxia

    2016-01-01

    To investigate the spread direction and prognostic factors in limb-onset sporadic amyotrophic lateral sclerosis (sALS). Medical records of 128 patients with sALS were reviewed. Variables studied were age at symptom onset, gender, region and lateralization of onset, onset to diagnosis interval (ODI), progression direction, bulbar-involved, time from onset to bulbar-involved, ALSFRS-r, upper motor neuron (UMN) signs and progression rate. First, the horizontal and vertical directions are major spreading directions in limb-onset sALS. Second, in crossed and interposed groups, while ODI is shorter, the progression rate is faster and UMN signs are more pronounced (p spread directions in limb-onset sALS. Except for ALSFRS-r and ODI, bulbar-involved is an adverse factor for ALS progression, and progression rate is related to the time from onset symptoms to bulbar-involved. © 2016 S. Karger AG, Basel.

  4. Amnesia in Frontotemporal Dementia with Amyotrophic Lateral Sclerosis, Masquerading Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    A. Yamanami-Irioka

    2011-10-01

    Full Text Available A 68-year-old man with a clinical diagnosis of Alzheimer’s disease (AD later developed amyotrophic lateral sclerosis (ALS, which was confirmed at autopsy at age 72 years. Because neuronal loss and AD-type pathologies (Braak stage II for neurofibrillary tangles were scant, TDP-43-positive intracytoplasmic inclusions in hippocampal dentate granular cells and in neurons in the subiculum and amygdala, even though small in amount, may represent the earliest lesions of ALS-related dementia and could be the cause of dementia in this patient. Although the persistent elevation of creatine kinase from the onset could be a pointer to the presence of motor involvement, more accurate characterization of dementia, which may differentiate ALS-related dementia and AD, is necessary.

  5. Patients' self-perceived burden, caregivers' burden and quality of life for amyotrophic lateral sclerosis patients: a cross-sectional study.

    Science.gov (United States)

    Geng, Dan; Ou, RuWei; Miao, XiaoHui; Zhao, LiHong; Wei, QianQian; Chen, XuePing; Liang, Yan; Shang, HuiFang; Yang, Rong

    2017-10-01

    This study surveys the quality of life of amyotrophic lateral sclerosis patients and the factors associated with amyotrophic lateral sclerosis patients' self-perceived burden and their caregivers' burden. Burdens of patients with amyotrophic lateral sclerosis and their caregivers in Chinese population are largely unknown. A cross-sectional study was conducted among 81 pairs of amyotrophic lateral sclerosis patients and their caregivers. Amyotrophic lateral sclerosis patients' self-perceived burden and caregivers' burden were assessed by the Self-Perceived Burden Scale and Zarit-Burden Interview, respectively. Quality of life of amyotrophic lateral sclerosis patients was measured using the World Health Organization Quality of Life-Bref. The amyotrophic lateral sclerosis Functional Rating Scale-Revised questionnaire was used to estimate patients' physical function. Both patients and caregivers reported a mild to moderate burden. The World Health Organization quality of life-Bref scores were decreased in respondents with lower amyotrophic lateral sclerosis Functional Rating Scale-Revised, higher Self-Perceived Burden Scale and higher Zarit-Burden Interview scores. Self-Perceived Burden Scale scores were associated with patients' knowledge of amyotrophic lateral sclerosis, respiratory function and female sex. Zarit-Burden Interview scores were associated with caregivers' age, patients' motor function and out-of-pocket payment. With increase in amyotrophic lateral sclerosis patients' self-perceived burden and caregivers' burden, quality of life of amyotrophic lateral sclerosis patients decreased. Female patients, who had known more about the disease, and those with severe respiratory dysfunction were subject to higher self-perceived burden. Older caregivers and caregivers of patients with severe motor dysfunction and more out-of-pocket payment experienced more care burdens. Our study suggests that paying more attention to female amyotrophic lateral sclerosis patients

  6. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M.; McLaughlin, Russell L.; Diekstra, Frank P.; Pulit, Sara L.; van der Spek, Rick A. A.; Vosa, Urmo; de Jong, Simone; Robinson, Matthew R.; Yang, Jian; Fogh, Isabella; van Doormaal, Perry T. C.; Tazelaar, Gijs H. P.; Koppers, Max; Blokhuis, Anna M.; Sproviero, William; Jones, Ashley R.; Kenna, Kevin P.; van Eijk, Kristel R.; Harschnitz, Oliver; Schellevis, Raymond D.; Brands, William J.; Medic, Jelena; Menelaou, Androniki; Vajda, Alice; Ticozzi, Nicola; Lin, Kuang; Rogelj, Boris; Vrabec, Katarina; Ravnik-Glavac, Metka; Koritnik, Blazi; Zidar, Janez; Leonardis, Lea; Groselj, Leja Dolenc; Millecamps, Stephanie; Salachas, Francois; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-Garcia, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E.; Shaw, Pamela J.; Hardy, John; Orrell, Richard W.; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Topp, Simon; Petri, Susanne; Abdulla, Susanne; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Ophoff, Roel A.; Staats, Kim A.; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Basak, A. Nazli; Tunca, Ceren; Hamzeiy, Hamid; Parman, Yesim; Meitinger, Thomas; Lichtner, Peter; Radivojkov-Blagojevic, Milena; Andres, Christian R.; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A. M.; Saker-Delye, Safaa; Duerr, Alexandra; Wood, Nicholas W.; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Noethen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-Francois; Uitterlinden, Andre G.; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; Blauw, Hylke M.; van der Kooi, Anneke J.; de Visser, Marianne; Goris, An; Weber, Markus; Shaw, Christopher E.; Smith, Bradley N.; Pansarasa, Orietta; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P.; D'Alfonso, Sandra; Bertolin, Cinzia; Soraru, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simona; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Muller, Bernard; Stuit, Robbert Jan; Blair, Ian; Zhang, Katharine; McCann, Emily P.; Fifita, Jennifer A.; Nicholson, Garth A.; Rowe, Dominic B.; Pamphlett, Roger; Kiernan, Matthew C.; Grosskreutz, Julian; Witte, Otto W.; Ringer, Thomas; Prell, Tino; Stubendorff, Beatrice; Kurth, Ingo; Huebner, Christian A.; Leigh, P. Nigel; Casale, Federico; Chio, Adrian; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C.; Weishaupt, Jochen H.; Robberecht, Wim; Van Damme, Philip; Franke, Lude; Pers, Tune H.; Brown, Robert H.; Glass, Jonathan D.; Landers, John E.; Hardiman, Orla; Andersen, Peter M.; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; Wray, Naomi R.; Visscher, Peter M.; de Bakker, Paul I. W.; van Es, Michael A.; Pasterkamp, R. Jeroen; Lewis, Cathryn M.; Breen, Gerome; Al-Chalabi, Ammar; van den Berg, Leonard H.; Veldink, Jan H.

    To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577

  7. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M.; McLaughlin, Russell L.; Diekstra, Frank P.; Pulit, Sara L.; van der Spek, Rick A. A.; Võsa, Urmo; de Jong, Simone; Robinson, Matthew R.; Yang, Jian; Fogh, Isabella; van Doormaal, Perry Tc; Tazelaar, Gijs H. P.; Koppers, Max; Blokhuis, Anna M.; Sproviero, William; Jones, Ashley R.; Kenna, Kevin P.; van Eijk, Kristel R.; Harschnitz, Oliver; Schellevis, Raymond D.; Brands, William J.; Medic, Jelena; Menelaou, Androniki; Vajda, Alice; Ticozzi, Nicola; Lin, Kuang; Rogelj, Boris; Vrabec, Katarina; Ravnik-Glavač, Metka; Koritnik, Blaž; Zidar, Janez; Leonardis, Lea; Grošelj, Leja Dolenc; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E.; Shaw, Pamela J.; Hardy, John; Orrell, Richard W.; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Topp, Simon; Petri, Susanne; Abdulla, Susanne; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Ophoff, Roel A.; Staats, Kim A.; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; van Deerlin, Vivianna M.; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Basak, A. Nazli; Tunca, Ceren; Hamzeiy, Hamid; Parman, Yesim; Meitinger, Thomas; Lichtner, Peter; Radivojkov-Blagojevic, Milena; Andres, Christian R.; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A. M.; Saker-Delye, Safaa; Dürr, Alexandra; Wood, Nicholas W.; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöthen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G.; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; Blauw, Hylke M.; van der Kooi, Anneke J.; de Visser, Marianne; Goris, An; Weber, Markus; Shaw, Christopher E.; Smith, Bradley N.; Pansarasa, Orietta; Cereda, Cristina; del Bo, Roberto; Comi, Giacomo P.; D'alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simona; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Muller, Bernard; Stuit, Robbert Jan; Blair, Ian; Zhang, Katharine; McCann, Emily P.; Fifita, Jennifer A.; Nicholson, Garth A.; Rowe, Dominic B.; Pamphlett, Roger; Kiernan, Matthew C.; Grosskreutz, Julian; Witte, Otto W.; Ringer, Thomas; Prell, Tino; Stubendorff, Beatrice; Kurth, Ingo; Hübner, Christian A.; Leigh, P. Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C.; Weishaupt, Jochen H.; Robberecht, Wim; van Damme, Philip; Franke, Lude; Pers, Tune H.; Brown, Robert H.; Glass, Jonathan D.; Landers, John E.; Hardiman, Orla; Andersen, Peter M.; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; Wray, Naomi R.; Visscher, Peter M.; de Bakker, Paul I. W.; van Es, Michael A.; Pasterkamp, R. Jeroen; Lewis, Cathryn M.; Breen, Gerome; Al-Chalabi, Ammar; van den Berg, Leonard H.; Veldink, Jan H.

    2016-01-01

    To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577

  8. Targeted genetic screen in amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype

    NARCIS (Netherlands)

    Cooper-Knock, Johnathan; Robins, Henry; Niedermoser, Isabell; Wyles, Matthew; Heath, Paul R.; Higginbottom, Adrian; Walsh, Theresa; Kazoka, Mbombe; Al Kheifat, Ahmad; Al-Chalabi, Ammar; Basak, Nazli; Blair, Ian; Dekker, Annelot; Hardiman, Orla; Hide, Winston; Iacoangeli, Alfredo; Kenna, Kevin; Landers, John; McLaughlin, Russel; Mill, Jonathan; Middelkoop, Bas; Moisse, Mattieu; Pardina, Jesus Mora; Morrison, Karen; Newhouse, Stephen; Pulit, Sara; Shatunov, Aleksey; Shaw, Chris; Sproviero, William; Tazelaar, Gijs; van Damme, Philip; van den Berg, Leonard; van der Spek, Rick; Eijk, Kristelvan; van Es, Michael; van Rheenen, Wouter; van Vugt, Joke; Veldink, Jan; Kooyman, Maarten; Glass, Jonathan; Robberecht, Wim; Gotkine, Marc; Drory, Vivian; Kiernan, Matthew; Neto, Miguel Mitne; Ztaz, Mayana; Couratier, Philippe; Corcia, Philippe; Silani, Vincenzo; Chio, Adriano; de Carvalho, Mamede; Pinto, Susana; Redondo, Alberto Garcia; Andersen, Peter; Weber, Markus; Ticozzi, Nicola; Ince, Paul G.; Hautbergue, Guillaume M.; McDermott, Christopher J.; Kirby, Janine; Shaw, Pamela J.

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic

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

    NARCIS (Netherlands)

    Cudkowicz, Merit E.; van den Berg, Leonard H.; Shefner, Jeremy M.; Mitsumoto, Hiroshi; Mora, Jesus S.; Ludolph, Albert; Hardiman, Orla; Bozik, Michael E.; Ingersoll, Evan W.; Archibald, Donald; Meyers, Adam L.; Dong, Yingwen; Farwell, Wildon R.; Kerr, Douglas A.; Henderson, R.; Kiernan, M.; Mathers, S.; Vucic, S.; de Bleecker, J.; Robberecht, W.; Briemberg, H.; Genge, A.; Korngut, L.; Matte, G.; Shoesmith, C.; Zinman, L.; Camu, W.; Desnuelle, C.; Destee, A.; Meininger, V.; Pouget, J.; Grehl, T.; Grosskreutz, J.; Ludolph, A.; Meyer, T.; Petri, S.; Hardiman, O.; de Visser, M.; Voermans, N.; van den Berg, L.; de Rivera, F. J. R.; Gamez, J.; Carbonell, J. G.; Pardina, J. S. Mora; Povedano, M.; Persson, L.; Ronnevi, L.-O.; Al-Chalabi, A.; Morrison, K.; Shaw, P.; Talbot, K.; Williams, T.; Young, C.; Andrews, J.; Atassi, N.; Barohn, R.; Bedlack, R.; Boylan, K.; Bromberg, M.; Brooks, B.; Burns, T.; Caress, J.; Donofrio, P.; Gelinas, D.; Ginsburg, D.; Glass, J.; Goslin, K.; Heiman-Patterson, T.; Heitzman, D.; Jackson, C.; Katz, J.; Kolb, S.; Lacomis, D.; Ladha, S.; McCluskey, L.; Mitsumoto, H.; Morrison, B.; Mozaff, T.; Oskarsson, B.; Pascuzzi, R.; Pattee, G.; Pestronk, A.; Pioro, E.; Rosenfeld, J.; Rudnicki, S.; Sharma, K.; Shefner, J.; Simmons, Z.; Simpson, E.; Sorenson, E.; Stommel, E.; Sufi, R.; Swenson, A.; Tiryaki, E.; Vu, T.; Weiss, M.

    2013-01-01

    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

  10. Reduced p75NTRexpression delays disease onset only in female mice of a transgenic model of familial amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Küst, B.M.; Brouwer, N.; Mantingh, I.J.; Boddeke, H.W.G.M.; Copray, J.C.V.M.

    2003-01-01

    hSOD1 (G93A) transgenic mice develop pathological changes similar to those in patients with familial amyotrophic lateral sclerosis (FALS). In particular, the progressive degeneration of motoneurons is charactered in this mouse model. One feature of stressed motoneurons in ALS and the hSOD1 mice is

  11. Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers

    NARCIS (Netherlands)

    Dekker, Annelot M.; Seelen, Meinie; van Doormaal, Perry T. C.; van Rheenen, Wouter; Bothof, Reinoud J. P.; van Riessen, Tim; Brands, William J.; van der Kooi, Anneke J.; de Visser, Marianne; Voermans, Nicol C.; Pasterkamp, R. Jeroen; Veldink, Jan H.; van den Berg, Leonard H.; van Es, Michael A.

    2016-01-01

    Sporadic amyotrophic lateral sclerosis (ALS) is considered to be a complex disease with multiple genetic risk factors contributing to the pathogenesis. Identification of genetic risk factors that co-occur frequently could provide relevant insight into underlying mechanisms of motor neuron

  12. Comparing methods to combine functional loss and mortality in clinical trials for amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    van Eijk RPA

    2018-03-01

    Full Text Available Ruben PA van Eijk,1 Marinus JC Eijkemans,2 Dimitris Rizopoulos,3 Leonard H van den Berg,4,* Stavros Nikolakopoulos5,* 1Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands; 2Department of Biostatistics, University Medical Center Utrecht, Utrecht, the Netherlands; 3Department of Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands; 4Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands; 5Department of Biostatistics, University Medical Center Utrecht, Utrecht, the Netherlands *These authors contributed equally to this work Objective: Amyotrophic lateral sclerosis (ALS clinical trials based on single end points only partially capture the full treatment effect when both function and mortality are affected, and may falsely dismiss efficacious drugs as futile. We aimed to investigate the statistical properties of several strategies for the simultaneous analysis of function and mortality in ALS clinical trials. Methods: Based on the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT database, we simulated longitudinal patterns of functional decline, defined by the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R and conditional survival time. Different treatment scenarios with varying effect sizes were simulated with follow-up ranging from 12 to 18 months. We considered the following analytical strategies: 1 Cox model; 2 linear mixed effects (LME model; 3 omnibus test based on Cox and LME models; 4 composite time-to-6-point decrease or death; 5 combined assessment of function and survival (CAFS; and 6 test based on joint modeling framework. For each analytical strategy, we calculated the empirical power and sample size. Results: Both Cox and LME models have increased false-negative rates when treatment exclusively affects either function or survival. The joint model has superior power compared to other strategies. The composite end point

  13. Coping strategies and psychological distress in caregivers of patients with Amyotrophic Lateral Sclerosis (ALS).

    Science.gov (United States)

    Siciliano, Mattia; Santangelo, Gabriella; Trojsi, Francesca; Di Somma, Carmela; Patrone, Manila; Femiano, Cinzia; Monsurrò, Maria Rosaria; Trojano, Luigi; Tedeschi, Gioacchino

    2017-08-01

    Amyotrophic lateral sclerosis (ALS) causes distress in caregivers. The present study aims to examine the association between coping strategies and psychological distress in caregivers of ALS patients. Coping strategies were assessed in 96 ALS informal caregivers by means of the Coping Inventory for Stressful Situations. Data about caregivers' demographic characteristics, levels of burden, depression and anxiety (psychological distress) were also gathered by standardised questionnaires. Patients' clinical, cognitive and behavioural disturbances were evaluated by ALS specific assessment tools. Sequential logistic regression analysis showed that emotion-oriented coping strategy was significantly associated with high levels of depressive (p ALS caregivers. These findings suggest that interventions aimed at reducing utilisation of maladaptive coping strategies may improve well-being in ALS caregivers, and, possibly, management of symptoms in ALS patients.

  14. Participation restrictions in ambulatory amyotrophic lateral sclerosis patients: Physical and psychological factors.

    Science.gov (United States)

    Van Groenestijn, Annerieke C; Schröder, Carin D; Kruitwagen-Van Reenen, Esther T; Van Den Berg, Leonard H; Visser-Meily, Johanna M A

    2017-11-01

    The aim of this study was to assess the prevalence of participation restrictions in ambulatory patients with amyotrophic lateral sclerosis (ALS) and to identify physical and psychological contributory factors. In this cross-sectional study, self-reported participation restrictions of 72 ambulatory ALS patients were assessed using the social health status dimension (SIPSOC) of the Sickness Impact Profile (SIP-68). Associations between SIPSOC and physical functioning, psychological factors, and demographic factors were analyzed using hierarchical regression analyses. Ninety-two percent of the patients reported participation restrictions; 54.9% could be explained by physical functioning; psychological factors accounted for 8.1% of the variance. Lung capacity, functional mobility, fatigue, and helplessness were independently associated with participation restrictions. Ambulatory ALS patients have participation restrictions, which may be influenced if early ALS care is directed toward lung capacity, functional mobility, fatigue, and feelings of helplessness. Muscle Nerve 56: 912-918, 2017. © 2017 Wiley Periodicals, Inc.

  15. Glutamate and aspartate are decreased in the skin in amyotrophic lateral sclerosis

    Science.gov (United States)

    Ono, S.; Yamauchi, M.

    1992-01-01

    We measured the levels of amino acids in biopsied skin from eight patients with amyotrophic lateral sclerosis (ALS) and seven controls. The most conspicuous changes in ALS patients were as follows. First, the contents of the acidic amino acids glutamate and aspartate were significantly decreased in ALS, and were negatively and significantly associated with the duration of illness. Second, the levels of the collagen-associated amino acids hydroxyproline, proline, glycine, alanine, and hydroxylysine were significantly decreased in ALS, and correlated inversely with the duration of illness. These results suggest that there are abnormalities of acidic amino acids and collagen-associated amino acids in the skin of patients with ALS. These changes may underlie the pathogenesis of ALS.

  16. Fine-Tuning ER Stress Signal Transducers to Treat Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Danilo B. Medinas

    2017-07-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease characterized by the progressive loss of motoneurons and paralysis. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting disturbances in motoneuron proteostasis. Endoplasmic reticulum (ER stress has emerged as an early pathogenic event underlying motoneuron vulnerability and denervation in ALS. Maintenance of ER proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR. Inositol-requiring enzyme 1 (IRE1 is an ER-located kinase and endoribonuclease that operates as a major ER stress transducer, mediating the establishment of adaptive and pro-apoptotic programs. Here we discuss current evidence supporting the role of ER stress in motoneuron demise in ALS and build the rational to target IRE1 to ameliorate neurodegeneration.

  17. Epidemiology of amyotrophic lateral sclerosis patients in a centre in Buenos Aires

    Directory of Open Access Journals (Sweden)

    Mariela Bettini

    2011-12-01

    Full Text Available Sporadic amyotrophic lateral sclerosis (sALS is considered a multifactorial disease with genetic and environmental factors causing motor neuron degeneration. OBJECTIVE: To describe the epidemiological and occupational characteristics of patients with sALS who attended the Ramos Mejía Hospital at Buenos Aires, Argentina. METHOD: We analyzed the medical records of sALS patients diagnosed between 2001 and 2008. All occupations were coded according to the International Standard Classification of Occupation (ISCO. RESULTS: 187 patients were assessed, 38.5% were women and 61.5% men. Mean age at diagnosis was 55 years. 16% of them came from rural areas; 68% of the studied population had no health insurance. 40% were employed in elementary occupations, 19 were technicians and 8 handicraftsmen. CONCLUSION: The most represented profession was elementary occupation. A large proportion of patients came from rural areas, which might suggest an increased risk of environmental exposure to an unknown agent in those regions.

  18. Pulseless electrical activity during general anesthesia induction in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    You, Tae Min; Kim, Seungoh

    2017-09-01

    Pulseless electrical activity (PEA) is a clinical condition characterized by unresponsiveness and lack of palpable pulse in the presence of organized cardiac electrical activity and is caused by a profound cardiovascular insult (e.g., severe prolonged hypoxia or acidosis, extreme hypovolemia, or flow-restricting pulmonary embolus). Amyotrophic lateral sclerosis (ALS) is a disease that is characterized by progressive degeneration of all levels of the motor nervous system. Damage to the respiratory system and weakness of the muscles may increase the likelihood of an emergency situation occurring in patients with ALS while under general anesthesia. We report a case of PEA during the induction of general anesthesia in a patient with ALS who presented for dental treatment and discuss the causes of PEA and necessary considerations for general anesthesia in patients with ALS.

  19. Mechanisms of Neuroprotection by Protein Disulphide Isomerase in Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Adam K. Walker

    2011-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating neurodegenerative disease characterised by the progressive loss of motor neurons, leading to paralysis and death within several years of onset. Although protein misfolding is a key feature of ALS, the upstream triggers of disease remain elusive. Recently, endoplasmic reticulum (ER stress was identified as an early and central feature in ALS disease models as well as in human patient tissues, indicating that ER stress could be an important process in disease pathogenesis. One important chaperone induced by ER stress is protein disulphide isomerase (PDI, which is both upregulated and posttranslationally inhibited by S-nitrosylation in ALS. In this paper, we present evidence from studies of genetics, model organisms, and patient tissues which indicate an active role for PDI and ER stress in ALS disease processes.

  20. Electrical Impedance Myography (EIM) in the Evaluation of the Tongue Musculature in Amyotrophic Lateral Sclerosis (ALS)

    Science.gov (United States)

    Shellikeri, Sanjana; Yunusova, Yana; Green, Jordan R.; Pattee, Gary L.; Berry, James D.; Rutkove, Seward B.; Zinman, Lorne

    2015-01-01

    Introduction Electrical impedance myography (EIM) quantifies muscle health and is used as a biomarker of muscle abnormalities in neurogenic and myopathic diseases. EIM has yet to be evaluated in the tongue musculature in people with amyotrophic lateral sclerosis (ALS), who often show clinical bulbar signs. Methods The lingual musculature of 19 subjects with motor neuron disease and 21 of normal participants were assessed using EIM, strength and endurance testing, and clinical observation. Results Tongue musculature in the ALS group was characterized by significantly smaller phase (Ph) and larger resistance (R) when compared to the healthy cohort. Ph and tongue endurance were correlated in the ALS group. Discussion EIM of tongue musculature could distinguish people with ALS from healthy controls. The demonstrated relationship between tongue function and Ph supports further testing of EIM of the tongue as a potential biomarker in ALS. PMID:25580728

  1. Electrical impedance myography in the evaluation of the tongue musculature in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Shellikeri, Sanjana; Yunusova, Yana; Green, Jordan R; Pattee, Gary L; Berry, James D; Rutkove, Seward B; Zinman, Lorne

    2015-10-01

    Electrical impedance myography (EIM) quantifies muscle health and is used as a biomarker of muscle abnormalities in neurogenic and myopathic diseases. EIM has yet to be evaluated in the tongue musculature in patients with amyotrophic lateral sclerosis (ALS), who often show clinical bulbar signs. The lingual musculature of 19 subjects with motor neuron disease and 21 normal participants was assessed using EIM, strength and endurance testing, and clinical assessment. Tongue musculature in the ALS group was characterized by significantly smaller phase (Ph) and greater resistance (R) when compared with the healthy cohort. Ph and tongue endurance were correlated in the ALS group. EIM of tongue musculature could distinguish those with ALS from healthy controls. The demonstrated relationship between tongue function and Ph supports further testing of EIM of the tongue as a potential biomarker in ALS. © 2015 Wiley Periodicals, Inc.

  2. Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

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    Jia Liu

    2017-08-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive neurodegenerative disease that affects upper motor neurons (MNs comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining MNs in ALS patients and animal models of the disease.

  3. Intraspinal stem cell transplantation for amyotrophic lateral sclerosis: Ready for efficacy clinical trials?

    Science.gov (United States)

    Atassi, Nazem; Beghi, Ettore; Blanquer, Miguel; Boulis, Nicholas M; Cantello, Roberto; Caponnetto, Claudia; Chiò, Adriano; Dunnett, Stephen B; Feldman, Eva L; Vescovi, Angelo; Mazzini, Letizia

    2016-12-01

    Intraspinal stem cell (SC) transplantation represents a new therapeutic approach for amyotrophic lateral sclerosis (ALS) clinical trials. There are considerable difficulties in designing future efficacy trials, some related to the field of ALS and some that are specific to SCs or the mode of delivery. In October 2015, the most controversial points on SC transplantation were addressed during an international workshop intended to bring together international SC and ALS researchers in a public discussion on a topic for which expertise is limited. During the meeting, a discussion was started on the basic structure of the ideal clinical trial testing the efficacy and safety of SC transplantation. The current document includes a number of consensus points reflecting the design of phase II/III clinical trials. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  4. Preservation of the nucleus X-pelvic floor motosystem in amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Schrøder, H D; Reske-Nielsen, E

    1984-01-01

    were observed in Onuf's nucleus X, not even in 8 cases in which other caudal motoneuron nuclei presented a severe loss of neurons. The striated sphincters proper demonstrated no signs of neurogenic atrophy in contrast to muscles in the limbs. The bulbo- and ischiocavernosus muscles, also supposedly......Fourteen cases of amyotrophic lateral sclerosis (ALS) were investigated neuropathologically, emphazising the sacral spinal cord which contains Onuf's nucleus X. The nucleus innervates the pelvic sphincters. In two cases, small striated pelvic muscles were studied. No changes characteristic of ALS...... innervated by Onuf's nucleus, were without pathological changes. Moreover, the latter two muscles were found to have a composition very similar to that of the sphincters. This indicates that a characteristic morphology of the nucleus X-innervated muscles exists. A review of the clinical records of all...

  5. [Noninvasive intermittent self-ventilation as a palliative measure in amyotrophic lateral sclerosis].

    Science.gov (United States)

    Schlamp, V; Karg, O; Abel, A; Schlotter, B; Wasner, M; Borasio, G D

    1998-12-01

    Almost all patients with amyotrophic lateral sclerosis (ALS) experience symptoms of nocturnal hypoventilation during the course of the illness. These symptoms can develop years before death and may severely affect quality of life. Non-invasive intermittent home mechanical ventilation (HMV) via mask is a possible palliative measure for these symptoms, which is not often used in Germany. We report on our experience with HMV in 24 patients with ALS. Our data show a good palliative effect in 17 of 24 treated patients. Severe complications did not occur. The mean ventilation time at present is 14 months. Available options and their consequences need to be discussed in detail with patients and relatives before HMV is initiated.

  6. CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs

    Directory of Open Access Journals (Sweden)

    Lixia Wang

    2017-04-01

    Full Text Available Abstract Amyotrophic lateral sclerosis (ALS is a complex neurodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells (iPSCs from fibroblasts of familial ALS patients bearing SOD1 +/A272C and FUS +/G1566A mutations, respectively. We further generated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing (RNA-seq analysis of motor neurons derived from SOD1 +/A272C and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.

  7. Onset and spreading patterns of upper and lower motor neuron symptoms in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Körner, Sonja; Kollewe, Katja; Fahlbusch, Marion; Zapf, Antonia; Dengler, Reinhard; Krampfl, Klaus; Petri, Susanne

    2011-05-01

    The potential linkage between upper (UMN) and lower motor neuron (LMN) involvement in amyotrophic lateral sclerosis (ALS) has not yet been fully elucidated. There is ongoing discussion as to whether ALS is primarily a disease of UMNs or LMNs. We performed a retrospective analysis of 189 ALS patients from our ALS outpatient database to investigate the different spreading patterns of UMN and LMN affection in disease progression in relation to the onset region. The body region with the highest UMN involvement at onset in general also had the highest frequency of LMN signs and vice versa. This is in line with the hypothesis of a focal onset of disease, which then spreads to adjacent areas. However, there was a great variation between ALS phenotypes. These observations support the hypothesis of focal damage of a localized group of motor neurons, which then spreads to adjacent motor neurons. Copyright © 2010 Wiley Periodicals, Inc.

  8. Predictive genetic testing for amyotrophic lateral sclerosis and frontotemporal dementia: genetic counselling considerations.

    Science.gov (United States)

    Crook, Ashley; Williams, Kelly; Adams, Lorel; Blair, Ian; Rowe, Dominic B

    2017-11-01

    Once a gene mutation that is causal of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) is identified in a family, relatives may decide to undergo predictive genetic testing to determine whether they are at risk of developing disease. Recent advances in gene discovery have led to a pressing need to better understand the implications of predictive genetic testing. Here we review the uptake of genetic counselling, predictive and reproductive testing, and the factors that impact the decision to undergo testing, for consideration in clinical practice. The literature suggests that the factors impacting the decision to undergo testing are complex due to the nature of these diseases, absence of available preventative medical treatment and variable age of onset in mutation carriers. Gaining further insight into the decision-making process and the impact of testing is critical as we seek to develop best-practice guidelines for predictive testing for familial ALS and FTD.

  9. Meditation training for people with amyotrophic lateral sclerosis and their caregivers.

    Science.gov (United States)

    Pagnini, Francesco; Di Credico, Chiara; Gatto, Ramona; Fabiani, Viviana; Rossi, Gabriella; Lunetta, Christian; Marconi, Anna; Fossati, Federica; Castelnuovo, Gianluca; Tagliaferri, Aurora; Banfi, Paolo; Corbo, Massimo; Sansone, Valeria; Molinari, Enrico; Amadei, Gherardo

    2014-04-01

    Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that is clinically characterized by progressive weakness leading to death by respiratory insufficiency, usually within three years. Although the patient's intellect and personality usually remain unimpaired, as the disease progresses, the patient becomes immobile, develops wasting, and speech becomes impaired, often resulting in social isolation and a high degree of psychological suffering. Mindfulness meditation has proven to be effective technique for reducing distress in many chronic diseases. However, to date, no study has investigated the effect of mindfulness meditation on patients with ALS. A mindfulness meditation training program for ALS patients needs to consider the particularities of ALS symptoms, including the loss of muscular functions and difficulties in respiration, together with the subsequent emotional impairments. With these caveats in mind, a modified protocol, based on original mindfulness meditation interventions, has been created specifically for the ALS population. This article describes the protocol and preliminary results.

  10. Comparison of psychosocial factors between patients with benign fasciculations and those with amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Rana Sandeep

    2009-01-01

    Full Text Available In this retrospective study, we compared the initial presentation of patients who were eventually diagnosed with either benign fasciculations (BF or amyotrophic lateral sclerosis (ALS. We found a significantly higher number of patients with BF reporting a past history of psychiatric symptoms, life stressors, and concurrent psychosomatic symptoms. There was no difference between the two groups in patient report of current anxiety or depression symptoms. These findings support our hypothesis that BF are a manifestation of psychological distress due to somatization and that reviewing psychosocial history is important when patients are being evaluated for fasciculations. Patients seeking medical attention for fasciculations and who do not report a history of underlying psychiatric or psychosomatic disorders should be followed closely as fasciculations have been reported to be a presenting feature of ALS.

  11. IgG from amyotrophic lateral sclerosis affects tubular calcium channels of skeletal muscle.

    Science.gov (United States)

    Delbono, O; García, J; Appel, S H; Stefani, E

    1991-06-01

    Amyotrophic lateral sclerosis (ALS) is a devastating human disease of upper and lower motoneurons. We studied the action of the immunoglobulin G (IgG) from ALS and disease control patients on dihydropyridine (DHP)-sensitive Ca2+ channels in single mammalian skeletal muscle fibers with the double Vaseline gap technique. The peak of the Ca2+ current (ICa) and the charge movement were reduced when the fibers were incubated in ALS IgG. These effects were lost when the IgG was boiled or adsorbed with skeletal tubular membranes. ALS IgG reduced skeletal muscle ICa in a similar fashion as nifedipine; the ICa blockade was voltage dependent, and the associated charge movement was reduced. These observations suggest that IgG from ALS patients reacts with the skeletal muscle DHP-sensitive Ca2+ channels or some associated regulatory moiety.

  12. Cardiac Failure as an Unusual Presentation in a Patient with History of Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Mohammad Hasan Namazi

    2014-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is the most well-known form of motor neuron diseases in which both upper and lower motor neurons are involved in this disease. We presented an unusual case of ALS whom had presented with chief complaint of dyspnea. Cardiac failure was diagnosed at the final stage of the ALS disease. The pathogenetic mechanism leading to an elevated occurrence of cardiomyopathy in ALS is not comprehensible. Dilated cardiomyopathy has been explained in some previous studies. Based on the collected data, it was hypothesized that cardiomyopathy is underdiagnosed in the ALS population, probably because symptoms are masqueraded as a result of the patients’ disability. It was suggested that in all motor neuron diseases a serial cardiological evaluation should be executed, including annual echocardiography.

  13. Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?

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    Sabrina Giacoppo

    2016-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic ap-proaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids.

  14. Specific Physical Exercise Improves Energetic Metabolism in the Skeletal Muscle of Amyotrophic-Lateral- Sclerosis Mice

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    Céline Desseille

    2017-10-01

    Full Text Available Amyotrophic Lateral Sclerosis is an adult-onset neurodegenerative disease characterized by the specific loss of motor neurons, leading to muscle paralysis and death. Although the cellular mechanisms underlying amyotrophic lateral sclerosis (ALS-induced toxicity for motor neurons remain poorly understood, growing evidence suggest a defective energetic metabolism in skeletal muscles participating in ALS-induced motor neuron death ultimately destabilizing neuromuscular junctions. In the present study, we report that a specific exercise paradigm, based on a high intensity and amplitude swimming exercise, significantly improves glucose metabolism in ALS mice. Using physiological tests and a biophysics approach based on nuclear magnetic resonance (NMR, we unexpectedly found that SOD1(G93A ALS mice suffered from severe glucose intolerance, which was counteracted by high intensity swimming but not moderate intensity running exercise. Furthermore, swimming exercise restored the highly ALS-sensitive tibialis muscle through an autophagy-linked mechanism involving the expression of key glucose transporters and metabolic enzymes, including GLUT4 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH. Importantly, GLUT4 and GAPDH expression defects were also found in muscles from ALS patients. Moreover, we report that swimming exercise induced a triglyceride accumulation in ALS tibialis, likely resulting from an increase in the expression levels of lipid transporters and biosynthesis enzymes, notably DGAT1 and related proteins. All these data provide the first molecular basis for the differential effects of specific exercise type and intensity in ALS, calling for the use of physical exercise as an appropriate intervention to alleviate symptoms in this debilitating disease.

  15. Positive effects of tertiary centres for amyotrophic lateral sclerosis on outcome and use of hospital facilities.

    Science.gov (United States)

    Chiò, A; Bottacchi, E; Buffa, C; Mutani, R; Mora, G

    2006-08-01

    To evaluate the effects of tertiary centres for amyotrophic lateral sclerosis (ALS) on ALS outcome and the use of hospital facilities. The study was based on the data of an epidemiological, prospective, population-based register on ALS (Piemonte and Valle d'Aosta Register for amyotrophic lateral sclerosis, PARALS). The 221 patients recruited between 1995 and 1996 were prospectively followed up for outcome and use of hospital-based services. In all, 97 patients were followed up by tertiary ALS centres and 124 by general neurological clinics. Patients followed up by tertiary ALS centres were found to be 4 years younger and underwent percutaneous endoscopic gastronomy and non-invasive positive-pressure ventilation more often. Patients followed up by tertiary ALS centres were found to have a considerably longer median survival time (1080 v 775 days), even when stratifying by age, site of onset and respiratory function at diagnosis. In Cox multivariate analysis, attending a tertiary ALS centre was observed to be an independent positive prognostic factor. Moreover, patients attending a tertiary ALS centre were admitted to hospital less often (1.2 v 3.3) and were more frequently admitted for planned interventions. Conversely, patients followed up by general neurological clinics were more frequently admitted for acute events. Also, the hospital stay was considerably shorter for patients attending tertiary ALS centres (5.8 v 12.4 days). Improved survival was seen in patients with ALS attending tertiary ALS centres, independently from all other known prognostic factors, possibly through a better implementation of supportive treatments. Moreover, because of these centres, the hospitalisation rate was markedly reduced, thus offering a cost-effective service to patients with ALS and to the community as a whole.

  16. Structural and diffusion imaging versus clinical assessment to monitor amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Arturo Cardenas-Blanco

    2016-01-01

    Full Text Available Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects upper and lower motor neurons. Observational and intervention studies can be tracked using clinical measures such as the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R but for a complete understanding of disease progression, objective in vivo biomarkers of both central and peripheral motor pathway pathology are highly desirable. The aim of this study was to determine the utility of structural and diffusion imaging as central nervous system biomarkers compared to the standard clinical measure, ALSFRS-R, to track longitudinal evolution using three time-point measurements. N = 34 patients with ALS were scanned and clinically assessed three times at a mean of three month time intervals. The MRI biomarkers were structural T1-weighted volumes for cortical thickness measurement as well as deep grey matter volumetry, voxel-based morphometry and diffusion tensor imaging (DTI. Cortical thickness focused specifically on the precentral gyrus while quantitative DTI biomarkers focused on the corticospinal tracts. The evolution of imaging biomarkers and ALSFRS-R scores over time were analysed using a mixed effects model that accounted for the scanning interval as a fixed effect variable, and, the initial measurements and time from onset as random variables. The mixed effects model showed a significant decrease in the ALSFRS-R score, (p  0.5. In addition, deep grey matter volumetry and voxel-based morphometry also identified no significant changes. Furthermore, the availability of three time points was able to indicate that there was a linear progression in both clinical and fractional anisotropy measures adding to the validity of these results. The results indicate that DTI is clearly a superior imaging marker compared to atrophy for tracking the evolution of the disease and can act as a central nervous biomarker in longitudinal studies. It

  17. Riluzole 5 mg/mL oral suspension: for optimized drug delivery in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Dyer AM

    2016-12-01

    Full Text Available Ann Margaret Dyer, Alan Smith PharmaSci Consulting Limited, Nottingham, UK Abstract: The aim of the present work is to extensively evaluate the pharmaceutical attributes of currently available riluzole presentations. The article describes the limitations and risks associated with the administration of crushed tablets, including the potential for inaccurate dosing and reduced rate of absorption when riluzole is administered with high-fat foods, and the advantages that a recently approved innovative oral liquid form of riluzole confers on amyotrophic lateral sclerosis (ALS patients. The article further evaluates the patented and innovative controlled flocculation technology used in the pseudoplastic suspension formulation to reduce the oral anesthesia seen with crushed tablets, resulting in optimized drug delivery for riluzole. Riluzole is the only drug licensed for treating ALS, which is the most common form of motor neurone disease and a highly devastating neurodegenerative condition. The licensed indication is to extend life or the time to mechanical ventilation. Until recently, riluzole was only available as an oral tablet dosage form in the UK; however, an innovative oral liquid form, Teglutik® 5 mg/mL oral suspension, is now available. An oral liquid formulation provides an important therapeutic option for patients with ALS, >80% of who may become unable to swallow solid oral dosage forms due to disease-related dysphagia. Prior to the launch of riluzole oral suspension, the only way for many patients to continue to take riluzole as their disease progressed was through crushed tablets. A novel suspension formulation enables more accurate dosing and consistent ongoing administration of riluzole. There are clear and important advantages such as enhanced patient compliance compared with crushed tablets administered with food or via an enteral feeding tube and the potential for an improved therapeutic outcome and enhanced quality of life for

  18. A prospective study of quality of life in amyotrophic lateral sclerosis patients.

    Science.gov (United States)

    Jakobsson Larsson, B; Ozanne, A G; Nordin, K; Nygren, I

    2017-12-01

    The aim of this prospective and longitudinal study was to describe individual quality of life in patients with amyotrophic lateral sclerosis (ALS) and its correlations with physical function and emotional well-being from diagnosis and over time. Thirty-six patients were included in the study. Individual quality of life was measured with the Schedule of Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW), illness severity was assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS FRS-R), and emotional distress was measured using the Hospital Anxiety and Depression Scale (HADS). Data were collected from diagnosis and thereafter, every six months for a period of two years. Twelve patients completed the 24-month follow-up. Family, friends and own physical health were important for overall quality of life, from diagnosis and during the disease progression. Most patients had good quality of life, which remained stable, despite changed physical functions. Several patients scored above the cut-off score for doubtful and clinical anxiety and depression early on after diagnosis, and there was a significant decrease in anxiety over time. Soon after diagnosis, there was a correlation between depression and quality of life. The family, social relations and own physical health are important for overall quality of life in patients with ALS. Thus, supporting the family and facilitating so that patients can continue to stay in contact with friends are important aspects during the disease. Conducting an early screening for depression can be important for preventing decreased quality of life. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Noninvasive ventilation in amyotrophic lateral sclerosis: effects on sleep quality and quality of life.

    Science.gov (United States)

    Vandoorne, Eva; Vrijsen, Bart; Belge, Catharina; Testelmans, Dries; Buyse, Bertien

    2016-12-01

    Little is known about the effects of noninvasive ventilation (NIV) on sleep quality in amyotrophic lateral sclerosis (ALS). We aim to evaluate the long-term effects of NIV on sleep quality and quality of life in patients with ALS. In this prospective observational study, 13 ALS patients were followed for one year after initiating NIV. We evaluated sleep quality, quality of life and functional status with several questionnaires: Epworth sleepiness Scale (ESS), Pittsburg sleep quality index (PSQI), Short Form 36 Health Questionnaire (SF-36), McGill Quality of Life questionnaire (McGillQoL) and revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores (ALSFRS-R). Median and interquartile range (IQR) at the start of NIV was 59 (53-65) years. The ALSFRS-R at start was 30 (24-37) (median, IQR), with three patients having severe bulbar impairment (ALSFRS-R-bulbar ≤ 9). The P a CO 2 at start of NIV treatment was 48 (43-52) mmHg (median, IQR). During the one-year follow-up period, a significant decrease in the ALSFRS-R was observed. The impact of NIV in a short term (1 month) revealed a statistically significant decrease in ESS, decrease in total PSQI and of four PSQI subscales and improvement of almost all subscales of the McGill questionnaire. Long-term analyses (9 months to 1 year) revealed that amelioration in ESS and total PSQI was sustained. We conclude that accurately titrated NIV in ALS patients can stabilize sleep quality and quality of life for at least one year, despite significant disease progression.

  20. Diffusion tensor tractography analysis of the corpus callosum fibers in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Kim, Jee-Eun; Oh, Jungsu S; Sung, Jung-Joon; Lee, Kwang-Woo; Song, In Chan; Hong, Yoon-Ho

    2014-07-01

    Involvement of the corpus callosum (CC) is reported to be a consistent feature of amyotrophic lateral sclerosis (ALS). We examined the CC pathology using diffusion tensor tractography analysis to identify precisely which fiber bundles are involved in ALS. Diffusion tensor imaging was performed in 14 sporadic ALS patients and 16 age-matched healthy controls. Whole brain tractography was performed using the multiple-region of interest (ROI) approach, and CC fiber bundles were extracted in two ways based on functional and structural relevance: (i) cortical ROI selection based on Brodmann areas (BAs), and (ii) the sulcal-gyral pattern of cortical gray matter using FreeSurfer software, respectively. The mean fractional anisotropy (FA) values of the CC fibers interconnecting the primary motor (BA4), supplementary motor (BA6), and dorsolateral prefrontal cortex (BA9/46) were significantly lower in ALS patients than in controls, whereas those of the primary sensory cortex (BA1, BA2, BA3), Broca's area (BA44/45), and the orbitofrontal cortex (BA11/47) did not differ significantly between the two groups. The FreeSurfer ROI approach revealed a very similar pattern of abnormalities. In addition, a significant correlation was found between the mean FA value of the CC fibers interconnecting the primary motor area and disease severity, as assessed using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale, and the clinical extent of upper motor neuron signs. Our findings suggest that there is some degree of selectivity or a gradient in the CC pathology in ALS. The CC fibers interconnecting the primary motor and dorsolateral prefrontal cortices may be preferentially involved in ALS.

  1. Positron emission tomography neuroimaging in amyotrophic lateral sclerosis: what is new?

    International Nuclear Information System (INIS)

    Quartuccio, N.; Van Weehaeghe, D.; Van Laere, K.; Cistaro, A.; Jonsson, C.; Pagani, M.

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a neuro degenerative disease involving upper and lower motor neurons, extra-motor neurons, microglia and astrocytes. The neuro degenerative process results in progressive muscle paralysis and even in cognitive impairment. Within the complex diagnostic work-up, positron emission tomography (PET) represents a valuable imaging tool in the assessment of patients with ALS. PET, by means of different radiotracers (i.e. 18 F-fluorodeoxyglucose, 6-[ 18 F]fluoro-L-dopa, [ 11 C]flumazenil) can assess the status of the wide range of brain regions and neural circuits, which can be affected by ALS. Furthermore, experimental radio compounds have been developed for the evaluation of white matter, which plays a role in the progression of the disease. Here we present a comprehensive review including in different sections the most relevant PET studies: studies investigating ALS and ALS-mimicking conditions (especially primary lateral sclerosis and other neuro degenerative diseases), articles selecting specific subsets of patients (with bulbar or spinal onset), studies investigating patients with familial type of ALS, studies evaluating the role of the white matter in ALS and papers evaluating the diagnostic sensitivity of PET in ALS patients

  2. Biomarkers of Amyotrophic Lateral Sclerosis: Current Status and Interest of Oxysterols and Phytosterols

    Directory of Open Access Journals (Sweden)

    Anne Vejux

    2018-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a non-demyelinating neurodegenerative disease in adults with motor disorders. Two forms exist: a sporadic form (90% of cases and a family form due to mutations in more than 20 genes including the Superoxide dismutase 1, TAR DNA Binding Protein, Fused in Sarcoma, chromosome 9 open reading frame 72 and VAPB genes. The mechanisms associated with this pathology are beginning to be known: oxidative stress, glutamate excitotoxicity, protein aggregation, reticulum endoplasmic stress, neuroinflammation, alteration of RNA metabolism. In various neurodegenerative diseases, such as Alzheimer’s disease or multiple sclerosis, the involvement of lipids is increasingly suggested based on lipid metabolism modifications. With regard to ALS, research has also focused on the possible involvement of lipids. Lipid involvement was suggested for clinical arguments where changes in cholesterol and LDL/HDL levels were reported with, however, differences in positivity between studies. Since lipids are involved in the membrane structure and certain signaling pathways, it may be considered to look for oxysterols, mainly 25-hydroxycholesterol and its metabolites involved in immune response, or phytosterols to find suitable biomarkers for this pathology.

  3. Potassium channel abnormalities are consistent with early axon degeneration of motor axons in the G127X SOD1 mouse model of amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Maglemose, Rikke; Hedegaard, Anne; Lehnhoff, Janna

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease, which selectively affects upper and lower motoneurones. The underlying pathophysiology of the disease is complex but electrophysiological studies of peripheral nerves in ALS patients as well as human autopsy studies indicate...

  4. Nerve excitability changes related to axonal degeneration in amyotrophic lateral sclerosis: Insights from the transgenic SOD1(G127X) mouse model

    DEFF Research Database (Denmark)

    Moldovan, Mihai; Alvarez Herrero, Susana; Pinchenko, Volodymyr

    2012-01-01

    Motor nerve excitability studies by "threshold tracking" in amyotrophic lateral sclerosis (ALS) revealed heterogeneous abnormalities in motor axon membrane function possibly depending on disease stage. It remains unclear to which extent the excitability deviations reflect a pathogenic mechanism...

  5. No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy

    NARCIS (Netherlands)

    Seelen, Meinie; Visser, Anne E.; Overste, Daniel J.; Kim, Hong J.; Palud, A.; Wong, Tsz H.; van Swieten, John C.; Scheltens, Philip; Voermans, Nicol C.; Baas, Frank; de Jong, J. M. B. V.; van der Kooi, Anneke J.; de Visser, Marianne; Veldink, Jan H.; Taylor, J. Paul; van Es, Michael A.; van den Berg, Leonard H.

    2014-01-01

    Inclusion body myopathy (IBM) associated with Paget disease of the bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), sometimes called IBMPFD/ALS or multi system proteinopathy, is a rare, autosomal dominant disorder characterized by progressive degeneration of muscle,

  6. Effects of aerobic exercise therapy and cognitive behavioural therapy on functioning and quality of life in amyotrophic lateral sclerosis: protocol of the FACTS-2-ALS trial

    NARCIS (Netherlands)

    van Groenestijn, Annerieke C.; van de Port, Ingrid G. L.; Schröder, Carin D.; Post, Marcel W. M.; Grupstra, Hepke F.; Kruitwagen, Esther T.; van der Linde, Harmen; van Vliet, Reinout O.; van de Weerd, Margreet G. H.; van den Berg, Leonard H.; Lindeman, Eline

    2011-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting motor neurons in the spinal cord, brainstem and motor cortex, leading to muscle weakness. Muscle weakness may result in the avoidance of physical activity, which exacerbates disuse weakness and

  7. Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Ashworth, Nigel L; Satkunam, L E; Deforge, Dan

    2012-02-15

    Spasticity commonly affects patients with motor neuron disease. It is likely to contribute to worsening muscle dysfunction, increased difficulty with activities of daily living and deteriorating quality of life. This is an update of a review first published in 2003 and previously updated in 2005 and 2008. The objective of this review is to systematically review treatments for spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease. We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 July 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to July 2011), EMBASE (January 1980 to July 2011 ), CINAHL Plus (January 1937 to July 2011), AMED (January 1985 to July 2011) and LILACS (January 1982 to July 2011 ). We reviewed the bibliographies of the randomized controlled trials identified, and contacted authors and experts in the field. We included quasi-randomized or randomized controlled trials of participants with probable or definite amyotrophic lateral sclerosis according to the El Escorial diagnostic criteria (or a revised version) or the Airlie House revision. We would have included trials of physical therapy, modalities, prescription medications, non-prescription medications, chemical neurolysis, surgical interventions, and alternative therapies. Our primary outcome measure was reduction in spasticity at three months or greater as measured by the Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures were: validated measures based on history, physical examination, physiological measures, measures of function, measures of quality of life, all adverse events, and measures of cost. Two authors independently screened the abstracts of potential trials retrieved from the searches. Two authors extracted the data. We also contacted the author of the paper and obtained information not available in the published article. All three authors assessed the methodological quality of all included trials

  8. Depression and anxiety in a case series of amyotrophic lateral sclerosis: frequency and association with clinical features.

    Science.gov (United States)

    Prado, Laura de Godoy Rousseff; Bicalho, Isabella Carolina Santos; Vidigal-Lopes, Mauro; Prado, Vitor de Godoy Rousseff; Gomez, Rodrigo Santiago; de Souza, Leonardo Cruz; Teixeira, Antônio Lúcio

    2017-01-01

    To investigate the frequency of anxiety and depression and their association with clinical features of amyotrophic lateral sclerosis. This is a cross-sectional and descriptive study including a consecutive series of patients with sporadic amyotrophic lateral sclerosis according to Awaji's criteria. Patients underwent clinical and psychiatric assessment (anxiety and depression symptoms). We included 76 patients. The men/women ratio was 1.6:1. Participants' mean age at disease onset was 55 years (SD±12.1). Sixty-six patients (86.8%) were able to complete psychiatric evaluation. Clinically significant anxiety was found in 23 patients (34.8%) while clinically significant depression was found in 24 patients (36.4%). When we compared patients with and without depression a significant difference was seen only in the frequency of anxiety symptoms (pescala funcional. Foi encontrada correlação positiva entre os sintomas de ansiedade e depressão (pescala funcional.

  9. Neuroinflammation as the Proximate Cause of Signature Pathogenic Pattern Progression in Amyotrophic Lateral Sclerosis, Aids, and Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Lawrence M. Agius

    2012-01-01

    Full Text Available The realization of injury to large motor neurons is embedded within contextual reference to the parallel pathways of apoptosis and necrosis of system-patterned evolution. A widespread loss of cell components occurs intracellularly and involves a reactive participation to a neuroinflammation that potentially is immunologically definable. In such terms, sporadic and hereditary forms of amyotrophic sclerosis are paralleled by the components of a reactive nature that involve the aggregation of proteins and conformational misfolding on the one hand and a powerful oxidative degradation that overwhelms the proteasome clearance mechanisms. In such terms, global participation is only one aspect of a disorder realization that induces the development of the defining systems of modulation and of injury that involves the systems of consequence as demonstrated by the overwhelming immaturity of the molecular variants of mutated superoxide dismutase. It is further to such processes of neuroinflammatory consequence that the immune system is integral to the reactive involvement of neurons as patterns of disease recognition and as the system biology of prevalent voluntarily motor character. It is highly significant to recognize various inflammatory states in the nervous system as prototype variability in phenotype expression and as incremental progression in pathogenesis. In fact a determining definition of amyotrophic lateral sclerosis is an incremental phenotype modulation within the pathways of the consequential loss and depletion of motor cell components in the first instance. Neuroinflammation proves a pattern of the contextual spread of such pathogenic progression in the realization of end-stage injury states involving neurons and neuronal networks.

  10. Respiratory failure in a patient with antecedent poliomyelitis: amyotrophic lateral sclerosis or post-polio syndrome?

    Science.gov (United States)

    Terao, Shin-ichi; Miura, Naofumi; Noda, Aiji; Yoshida, Mari; Hashizume, Yoshio; Ikeda, Hiroshi; Sobue, Gen

    2006-10-01

    We report a 69-year-old man who developed paralytic poliomyelitis in childhood and then decades later suffered from fatal respiratory failure. Six months before this event, he had progressive weight loss and shortness of breath. He had severe muscular atrophy of the entire right leg as a sequela of the paralytic poliomyelitis. He showed mild weakness of the facial muscle and tongue, dysarthria, and severe muscle atrophy from the neck to proximal upper extremities and trunk, but no obvious pyramidal signs. Electromyogram revealed neurogenic changes in the right leg, and in the paraspinal, sternocleidomastoid, and lingual muscles. There was a slight increase in central motor conduction time from the motor cortex to the lumbar anterior horn. Pulmonary function showed restrictive ventilation dysfunction, which was the eventual cause of death. Some neuropathological features were suggestive of amyotrophic lateral sclerosis (ALS), namely Bunina bodies. In patients with a history of paralytic poliomyelitis who present after a long stable period with advanced fatal respiratory failure, one may consider not only respiratory impairment from post-polio syndrome but also the onset of ALS.

  11. Oral motor functions, speech and communication before a definitive diagnosis of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Makkonen, Tanja; Korpijaakko-Huuhka, Anna-Maija; Ruottinen, Hanna; Puhto, Riitta; Hollo, Kirsi; Ylinen, Aarne; Palmio, Johanna

    2016-01-01

    The aim of this study was to explore the cranial nerve symptoms, speech disorders and communicative effectiveness of Finnish patients with diagnosed or possible amyotrophic lateral sclerosis (ALS) at their first assessment by a speech-language pathologist. The group studied consisted of 30 participants who had clinical signs of bulbar deterioration at the beginning of the study. They underwent a thorough clinical speech and communication examination. The cranial nerve symptoms and ability to communicate were compared in 14 participants with probable or definitive ALS and in 16 participants with suspected or possible ALS. The initial type of ALS was also assessed. More deterioration in soft palate function was found in participants with possible ALS than with diagnosed ALS. Likewise, a slower speech rate combined with more severe dysarthria was observed in possible ALS. In both groups, there was some deterioration in communicative effectiveness. In the possible ALS group the diagnostic delay was longer and speech therapy intervention actualized later. The participants with ALS showed multidimensional decline in communication at their first visit to the speech-language pathologist, but impairments and activity limitations were more severe in suspected or possible ALS. The majority of persons with bulbar-onset ALS in this study were in the latter diagnostic group. This suggests that they are more susceptible to delayed diagnosis and delayed speech therapy assessment. It is important to start speech therapy intervention during the diagnostic processes particularly if the person already shows bulbar symptoms. Copyright © 2016. Published by Elsevier Inc.

  12. Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Baldinger, Reto; Katzberg, Hans Dieter; Weber, Markus

    2012-04-18

    Cramps are painful, involuntary muscle contractions. They commonly affect people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) at all stages of the disease. To date, the treatment of muscle cramps in ALS has been largely empirical without any evidence from randomised controlled trials. To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND. We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011), the Cochrane Central Register of Controlled Trials (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011) and reference lists of articles searched using the terms motor neuron disease, motor neurone disease, motoneuron disease or amyotrophic lateral sclerosis. We contacted authors of trials for further information. We included all randomised and quasi-randomised trials of oral medications in people with ALS which assessed cramps as a primary or secondary outcome measure or as an adverse event. We also included trials using subcutaneous or intravenous medications or physical therapy. All authors applied the selection criteria and assessed study quality independently, and all authors performed independent data extraction. Twenty studies including 4789 participants were identified. Only one trial, of tetrahydrocannabinol (THC), assessed cramps as the primary endpoint. Thirteen studies assessed cramps as a secondary endpoint. The medications comprised vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion. A meta-analysis of two small

  13. Disease-related changes in the cerebrospinal fluid metabolome in amyotrophic lateral sclerosis detected by GC/TOFMS.

    Directory of Open Access Journals (Sweden)

    Anna Wuolikainen

    2011-04-01

    Full Text Available The changes in the cerebrospinal fluid (CSF metabolome associated with the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS are poorly understood and earlier smaller studies have shown conflicting results. The metabolomic methodology is suitable for screening large cohorts of samples. Global metabolomics can be used for detecting changes of metabolite concentrations in samples of fluids such as CSF.Using gas chromatography coupled to mass spectrometry (GC/TOFMS and multivariate statistical modeling, we simultaneously studied the metabolome signature of ∼120 small metabolites in the CSF of patients with ALS, stratified according to hereditary disposition and clinical subtypes of ALS in relation to controls.The study is the first to report data validated over two sub-sets of ALS vs. control patients for a large set of metabolites analyzed by GC/TOFMS. We find that patients with sporadic amyotrophic lateral sclerosis (SALS have a heterogeneous metabolite signature in the cerebrospinal fluid, in some patients being almost identical to controls. However, familial amyotrophic lateral sclerosis (FALS without superoxide dismutase-1 gene (SOD1 mutation is less heterogeneous than SALS. The metabolome of the cerebrospinal fluid of 17 ALS patients with a SOD1 gene mutation was found to form a separate homogeneous group. Analysis of metabolites revealed that glutamate and glutamine were reduced, in particular in patients with a familial predisposition. There are significant differences in the metabolite profile and composition among patients with FALS, SALS and patients carrying a mutation in the SOD1 gene suggesting that the neurodegenerative process in different subtypes of ALS may be partially dissimilar.Patients with a genetic predisposition to amyotrophic lateral sclerosis have a more distinct and homogeneous signature than patients with a sporadic disease.

  14. Report by the Spanish Foundation for the Brain on the social impact of amyotrophic lateral sclerosis and other neuromuscular disorders.

    Science.gov (United States)

    Camacho, A; Esteban, J; Paradas, C

    A thorough knowledge of the socioeconomic scope of neuromuscular disease is essential for managing resources and raising social awareness. Our group reviewed current data on the epidemiology, mortality and dependence rates, and socioeconomic impact of amyotrophic lateral sclerosis and neuromuscular diseases in Spain. We also recorded how neurological care for these patients is organised. Neuromuscular disorders are a very heterogeneous group of diseases, and some are very rare. These disorders account for between 2.8% and 18% of the total motives for a neurological consultation. In Spain, prevalence and incidence figures for amyotrophic lateral sclerosis are similar to those in other countries; however, figures for patients with other neuromuscular diseases are not known. Since the diseases are chronic, progressive, and debilitating, they cause considerable disability and dependence, which in turn directly affects healthcare and social costs associated with the disease. The costs generated by one patient with amyotrophic lateral sclerosis or Duchenne disease have been calculated at about 50 000 euros per year. Neuromuscular disease shows aetiological, diagnostic, and prognostic complexity, and it requires multidisciplinary management. Follow-up for these patients should be entrusted to specialised units. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  15. Fruit and vegetable intake and risk of amyotrophic lateral sclerosis in Japan.

    Science.gov (United States)

    Okamoto, K; Kihira, T; Kobashi, G; Washio, M; Sasaki, S; Yokoyama, T; Miyake, Y; Sakamoto, N; Inaba, Y; Nagai, M

    2009-01-01

    There has been little interest in the role of nutrition in the prevention of amyotrophic lateral sclerosis (ALS). We investigated the relationship between dietary intake of vegetables, fruit, and antioxidants and the risk of ALS in Japan. Between 2000 and 2004, we recruited 153 ALS patients aged 18-81 years with disease duration of 3 years within the study period in accordance with El Escorial World Federation of Neurology criteria. Three hundred and six gender- and age-matched controls were randomly selected from the general population. Information on dietary factors was collected using a validated self-administered diet history questionnaire. A higher consumption of all fruits and vegetables and fruit alone in the highest quartiles was associated with a statistically significantly reduced risk of ALS. Although not statistically significant, a beneficial association between intake of all vegetables, green and yellow vegetables and other vegetables and ALS was found. No statistically significant dose-response relationship was observed between intake of beta-carotene, vitamin C and vitamin E and the risk of ALS. Our findings suggest that higher intake of food rich in antioxidants such as fruit and vegetables confer protection against the development of ALS.

  16. Inspiratory muscle training in patients with Amyotrophic Lateral Sclerosis: A systematic review.

    Science.gov (United States)

    Eidenberger, Margit; Nowotny, Silvia

    2014-01-01

    Amyotrophic Lateral Sclerosis is a neurodegenerative disease with rapid involvement of the inspiratory muscles, leading to respiratory insufficiency. Death often occurs by aspiration and pneumonia. Endurance- and strength therapy within ALS are discussed controversially. To review the current literature to assess the efficacy of inspiratory muscle training for ALS. Systematic review, using databases as PubMed, PEDro, Cochrane and Google Scholar. Inspiratory muscle training vs. sham training or inspiratory muscle training alone. Inspiratory muscle strength, dyspnoea, quality of life and survival time. Four studies could be included in this review, two RCT's, one pre-experimental study and one with a historical control group. In total 73 patients underwent inspiratory muscle training. Studies varied in onset of the training, the training protocol and the outcomes measured. At time, there is limited evidence that inspiratory muscle training leads to strengthening of inspiratory muscles in ALS. Improvements made were minor, in only a few parameters and also in control groups. Survival time was significantly longer in the experimental group in one study. Interesting suppositions (diaphragm training vs. other IM training, improvement of chest wall and lung compliance) need to be examined in robustly designed future trials, defining exact therapeutic windows and interventions.

  17. CRISPR/Cas9 Technology as an Emerging Tool for Targeting Amyotrophic Lateral Sclerosis (ALS).

    Science.gov (United States)

    Kruminis-Kaszkiel, Ewa; Juranek, Judyta; Maksymowicz, Wojciech; Wojtkiewicz, Joanna

    2018-03-19

    The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) is a genome editing tool that has recently caught enormous attention due to its novelty, feasibility, and affordability. This system naturally functions as a defense mechanism in bacteria and has been repurposed as an RNA-guided DNA editing tool. Unlike zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), CRISPR/Cas9 takes advantage of an RNA-guided DNA endonuclease enzyme, Cas9, which is able to generate double-strand breaks (DSBs) at specific genomic locations. It triggers cellular endogenous DNA repair pathways, contributing to the generation of desired modifications in the genome. The ability of the system to precisely disrupt DNA sequences has opened up new avenues in our understanding of amyotrophic lateral sclerosis (ALS) pathogenesis and the development of new therapeutic approaches. In this review, we discuss the current knowledge of the principles and limitations of the CRISPR/Cas9 system, as well as strategies to improve these limitations. Furthermore, we summarize novel approaches of engaging the CRISPR/Cas9 system in establishing an adequate model of neurodegenerative disease and in the treatment of SOD1-linked forms of ALS. We also highlight possible applications of this system in the therapy of ALS, both the inherited type as well as ALS of sporadic origin.

  18. Phenotypic differences of amyotrophic lateral sclerosis (ALS) in China and Germany.

    Science.gov (United States)

    Rosenbohm, Angela; Liu, Mingsheng; Nagel, Gabriele; Peter, Raphael S; Cui, Bo; Li, Xiaoguang; Kassubek, Jan; Rothenbacher, Dietrich; Lulé, Dorothée; Cui, Liying; Ludolph, Albert C

    2018-04-01

    The aim of this study is to explore phenotypical differences of amyotrophic lateral sclerosis (ALS) between two cohorts from Germany and China. Registry-based studies of ALS were conducted in South-West Germany from 2010 to 2014 and an ALS clinic in Beijing from 2013 to 2016, respectively. Demographic and clinical features of 663 German and 276 Chinese ALS patients were collected and compared. Mean age-at-onset was higher in German than in Chinese ALS patients [66.6 years (95% CI 65.7, 67.5) vs. 53.2 years (95% CI 52.0, 54.5)]. Age distribution of ALS patients peaked around 70-74 years in Germany and 50-54 years in China. Bulbar onset was more prevalent among German than among Chinese patients (35.9 vs. 22.8%). Diagnostic delay was higher in the Chinese than in the German study sample (12 vs. 5 months). Cognitive deficits were more pronounced in the Chinese cohort. Both cohorts differed in smoking habits, prevalence of diabetes and in body mass index (BMI). The apparent discrepancies between German and Chinese ALS patients (age at onset, gender distribution, bulbar forms, cognitive dysfunction, risk factors) reveal a quite different clinical phenotype in China, maybe due to socioeconomic status, environmental factors or genetic background. The observed differences in phenotype need to be pursued by further epidemiological studies on environmental and genetic risk factors.

  19. The established and emerging roles of astrocytes and microglia in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

    Directory of Open Access Journals (Sweden)

    Rowan Andrew Warren Radford

    2015-10-01

    Full Text Available Amyotrophic lateral sclerosis (ALS and Frontotemporal Dementia (FTD are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa, recent genetic discoveries conclusive link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72.The definitive aetiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarise the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterising these two disorders and may represent more effective interventions for disease progression and treatment options in the future.

  20. Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis.

    LENUS (Irish Health Repository)

    Byrne, Susan

    2010-11-03

    Background The population rate of familial amyotrophic lateral sclerosis (FALS) is frequently reported as 10%. However, a systematic review and meta-analysis of the true population based frequency of FALS has never been performed. Method A Medline literature review identified all original articles reporting a rate of FALS. Studies were grouped according to the type of data presented and examined for sources of case ascertainment. A systematic review and meta-analysis of reported rates of FALS was then conducted to facilitate comparison between studies and calculate a pooled rate of FALS. Results 38 papers reported a rate of FALS. Thirty-three papers were included in analysis and the rate of FALS for all studies was 4.6% (95% CI 3.9% to 5.5%). Restricting the analysis to prospective population based registry data revealed a rate of 5.1% (95% CI 4.1% to 6.1%). The incidence of FALS was lower in southern Europe. There was no correlation between rate of FALS and reported SOD1 mutation rates. Conclusion The rate of FALS among prospective population based registries is 5.1% (CI 4.1 to 6.1%), and not 10% as is often stated. Further detailed prospective population based studies of familial ALS are required to confirm this rate.

  1. Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis.

    LENUS (Irish Health Repository)

    Byrne, Susan

    2012-02-01

    BACKGROUND: The population rate of familial amyotrophic lateral sclerosis (FALS) is frequently reported as 10%. However, a systematic review and meta-analysis of the true population based frequency of FALS has never been performed. METHOD: A Medline literature review identified all original articles reporting a rate of FALS. Studies were grouped according to the type of data presented and examined for sources of case ascertainment. A systematic review and meta-analysis of reported rates of FALS was then conducted to facilitate comparison between studies and calculate a pooled rate of FALS. RESULTS: 38 papers reported a rate of FALS. Thirty-three papers were included in analysis and the rate of FALS for all studies was 4.6% (95% CI 3.9% to 5.5%). Restricting the analysis to prospective population based registry data revealed a rate of 5.1% (95% CI 4.1% to 6.1%). The incidence of FALS was lower in southern Europe. There was no correlation between rate of FALS and reported SOD1 mutation rates. CONCLUSION: The rate of FALS among prospective population based registries is 5.1% (CI 4.1 to 6.1%), and not 10% as is often stated. Further detailed prospective population based studies of familial ALS are required to confirm this rate.

  2. Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients

    KAUST Repository

    Conti, Antonio

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a severe and fatal neurodegenerative disease of still unknown pathogenesis. Recent findings suggest that the skeletal muscle may play an active pathogenetic role. To investigate ALS\\'s pathogenesis and to seek diagnostic markers, we analyzed skeletal muscle biopsies with the differential expression proteomic approach. We studied skeletal muscle biopsies from healthy controls (CN), sporadic ALS (sALS), motor neuropathies (MN) and myopathies (M). Pre-eminently among several differentially expressed proteins, Myosin binding protein H (MyBP-H) expression in ALS samples was anomalously high. MyBP-H is a component of the thick filaments of the skeletal muscle and has strong affinity for myosin, but its function is still unclear. High MyBP-H expression level was associated with abnormal expression of Rho kinase 2 (ROCK2), LIM domain kinase 1 (LIMK1) and cofilin2, that might affect the actin-myosin interaction. We propose that MyBP-H expression level serves, as a putative biomarker in the skeletal muscle, to discriminate ALS from motor neuropathies, and that it signals the onset of dysregulation in actin-myosin interaction; this in turn might contribute to the pathogenesis of ALS. © 2013 Elsevier B.V.

  3. Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Yoshiaki Furukawa

    2012-01-01

    Full Text Available Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1 gene cause a familial form of amyotrophic lateral sclerosis (ALS. While it remains controversial how SOD1 mutations lead to onset and progression of the disease, many in vitro and in vivo studies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations in sod1 gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

  4. Multi-disciplinary clinical protocol for the diagnosis of bulbar amyotrophic lateral sclerosis.

    Science.gov (United States)

    Chiaramonte, Rita; Di Luciano, Carmela; Chiaramonte, Ignazio; Serra, Agostino; Bonfiglio, Marco

    2018-04-23

    The objective of this study was to examine the role of different specialists in the diagnosis of amyotrophic lateral sclerosis (ALS), to understand changes in verbal expression and phonation, respiratory dynamics and swallowing that occurred rapidly over a short period of time. 22 patients with bulbar ALS were submitted for voice assessment, ENT evaluation, Multi-Dimensional Voice Program (MDVP), spectrogram, electroglottography, fiberoptic endoscopic evaluation of swallowing. In the early stage of the disease, the oral tract and velopharyngeal port were involved. Three months after the initial symptoms, most of the patients presented hoarseness, breathy voice, dysarthria, pitch modulation problems and difficulties in pronunciation of explosive, velar and lingual consonants. Values of MDVP were altered. Spectrogram showed an additional formant, due to nasal resonance. Electroglottography showed periodic oscillation of the vocal folds only during short vocal cycle. Swallowing was characterized by weakness and incoordination of oro-pharyngeal muscles with penetration or aspiration. A specific multidisciplinary clinical protocol was designed to report vocal parameters and swallowing disorders that changed more quickly in bulbar ALS patients. Furthermore, the patients were stratified according to involvement of pharyngeal structures, and severity index. Copyright © 2018 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. The Edinburgh Cognitive and Behavioural ALS Screen in a Chinese Amyotrophic Lateral Sclerosis Population.

    Science.gov (United States)

    Ye, Shan; Ji, Ying; Li, Chengyu; He, Ji; Liu, Xiaolu; Fan, Dongsheng

    2016-01-01

    The existing screening batteries assessing multiple neuropsychological functions are not specific to amyotrophic lateral sclerosis (ALS) patients and are limited to their physical dysfunctions, whereas category cognitive tests are too time-consuming to assess all the domains. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was recently developed as a fast and easy cognitive screening tool specifically designed for patients. The purpose of the study was to validate the effectiveness of the Chinese version in Chinese ALS populations. Eighty-four ALS patients and 84 age-, gender- and education-matched healthy controls were included in this cross-sectional study. All the participants took the ECAS, Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Primary caregivers of patients were interviewed for behavioural and psychiatric changes. Significant differences were noted in language (p = 0.01), fluency, executive function, ALS-specific functions, and ECAS total score (planguage function tended to be preserved in the higher education group. The average time of ECAS was only 18 minutes. The Chinese version of the ECAS is the first screening battery assessing multiple neuropsychological functions specially designed for the ALS population in China, which provides an effective and rapid tool to screen cognitive and behavioural impairments.

  6. Beyond the consensus criteria: multiple cognitive profiles in amyotrophic lateral sclerosis?

    Science.gov (United States)

    Consonni, Monica; Catricalà, Eleonora; Dalla Bella, Eleonora; Gessa, Valentina C; Lauria, Giuseppe; Cappa, Stefano F

    2016-08-01

    The Strong consensus recommendations (2009) propose behavioural (ALSbi) and/or dysexecutive (ALSci) impairment as the two main clinical profiles of non-motor manifestations in non-demented amyotrophic lateral sclerosis (ALS) patients. We aimed at assessing whether clustering pattern of neuropsychological performance of ALS patients suggest the existence of additional clinical syndromes beyond the currently recognized phenotypes. We applied principal component analysis (PCA) to a comprehensive neuropsychological evaluation of 71 non-demented ALS patients in order to identify clusters of variables correlating highly with each other, with the aim of detecting distinct patterns of neuropsychological test performance. The outcome of PCA demonstrated the existence of three main test clusters. Two, accounting for 27% of the patients, were compatible with the recognised ALSbi and ALSci profiles. An additional third cluster loaded on social cognition, language and memory tests and accounted for 24% of the patients. Of these, 15% had defective performance on at least two tests belonging to the latter non-executive cluster, and were thus unclassifiable according to current criteria. Our data-driven approach indicated a third dimension of cognitive impairment, including language, social cognition and episodic memory, as a distinct pattern of non-motor manifestations in ALS patients, in addition to the recognized ALSci and ALSbi profiles. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Predicting Early Bulbar Decline in Amyotrophic Lateral Sclerosis: A Speech Subsystem Approach

    Directory of Open Access Journals (Sweden)

    Panying Rong

    2015-01-01

    Full Text Available Purpose. To develop a predictive model of speech loss in persons with amyotrophic lateral sclerosis (ALS based on measures of respiratory, phonatory, articulatory, and resonatory functions that were selected using a data-mining approach. Method. Physiologic speech subsystem (respiratory, phonatory, articulatory, and resonatory functions were evaluated longitudinally in 66 individuals with ALS using multiple instrumentation approaches including acoustic, aerodynamic, nasometeric, and kinematic. The instrumental measures of the subsystem functions were subjected to a principal component analysis and linear mixed effects models to derive a set of comprehensive predictors of bulbar dysfunction. These subsystem predictors were subjected to a Kaplan-Meier analysis to estimate the time until speech loss. Results. For a majority of participants, speech subsystem decline was detectible prior to declines in speech intelligibility and speaking rate. Among all subsystems, the articulatory and phonatory predictors were most responsive to early bulbar deterioration; and the resonatory and respiratory predictors were as responsive to bulbar decline as was speaking rate. Conclusions. The articulatory and phonatory predictors are sensitive indicators of early bulbar decline due to ALS, which has implications for predicting disease onset and progression and clinical management of ALS.

  8. Is language impairment more common than executive dysfunction in amyotrophic lateral sclerosis?

    Science.gov (United States)

    Taylor, Lorna J; Brown, Richard G; Tsermentseli, Stella; Al-Chalabi, Ammar; Shaw, Christopher E; Ellis, Catherine M; Leigh, P Nigel; Goldstein, Laura H

    2013-05-01

    Systematic explorations of language abilities in patients with amyotrophic lateral sclerosis (ALS) are lacking in the context of wider cognitive change. Neuropsychological assessment data were obtained from 51 patients with ALS and 35 healthy controls matched for age, gender and IQ. Composite scores were derived for the domains of language and executive functioning. Domain impairment was defined as a composite score ≤5th centile relative to the control mean. Cognitive impairment was also classified using recently published consensus criteria. The patients with ALS were impaired on language and executive composite scores. Language domain impairment was found in 43% of patients with ALS, and executive domain impairment in 31%. Standardised language and executive composite scores correlated in the ALS group (r=0.68, pMultiple regression analyses indicated that scores on the executive composite accounted for 44% of the variance in language composite scores. Language impairments are at least as prevalent as executive dysfunction in ALS. While the two domains are strongly associated, executive dysfunction does not fully account for the profile of language impairments observed, further highlighting the heterogeneity of cognitive impairment in non-demented patients with ALS.

  9. Magnesium intake and risk of amyotrophic lateral sclerosis: results from five large cohort studies.

    Science.gov (United States)

    Fondell, Elinor; O'Reilly, Eilis J; Fitzgerald, Kathryn C; Falcone, Guido J; McCullough, Marjorie L; Park, Yikyung; Kolonel, Laurence N; Ascherio, Alberto

    2013-09-01

    A low magnesium intake has been suggested to be associated with amyotrophic lateral sclerosis (ALS) in pathological and case-control studies, but prospective studies in humans are lacking. The relation between dietary intake of magnesium and ALS risk was explored in five large prospective cohort studies (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health - AARP Diet and Health Study), comprising over 1,050,000 males and females contributing 1093 cases of ALS during a mean of 15 years of follow-up. Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model. Results demonstrated that dietary magnesium intake was not associated with ALS risk, relative risk 1.07, 95% confidence interval 0.88 - 1.31 comparing the highest quintile of intake with the lowest. This finding does not support a protective effect of magnesium intake on ALS risk. Further analyses should explore magnesium intake in combination with heavy metal exposure and genetic variants affecting magnesium absorption.

  10. Partial Block by Riluzole of Muscle Sodium Channels in Myotubes from Amyotrophic Lateral Sclerosis Patients

    Directory of Open Access Journals (Sweden)

    Cristina Deflorio

    2014-01-01

    Full Text Available Denervated muscles undergo fibrillations due to spontaneous activation of voltage-gated sodium (Na+ channels generating action potentials. Fibrillations also occur in patients with amyotrophic lateral sclerosis (ALS. Riluzole, the only approved drug for ALS treatment, blocks voltage-gated Na+ channels, but its effects on muscle Na+ channels and fibrillations are yet poorly characterized. Using patch-clamp technique, we studied riluzole effect on Na+ channels in cultured myotubes from ALS patients. Needle electromyography was used to study fibrillation potentials (Fibs in ALS patients during riluzole treatment and after one week of suspension. Patients were clinically characterized in all recording sessions. In myotubes, riluzole (1 μM, a therapeutic concentration reduced Na+ current by 20%. The rate of rise and amplitude of spikes evoked by depolarizing stimuli were also reduced. Fibs were detected in all patients tested during riluzole treatment and riluzole washout had no univocal effect. Our study indicates that, in human myotubes, riluzole partially blocks Na+ currents and affects action potentials but does not prevent firing. In line with this in vitro finding, muscle Fibs in ALS patients appear to be largely unaffected by riluzole.

  11. Early-Onset Alopecia and Amyotrophic Lateral Sclerosis: A Cohort Study

    Science.gov (United States)

    Fondell, Elinor; Fitzgerald, Kathryn C.; Falcone, Guido J.; O'Reilly, Éilis J.; Ascherio, Alberto

    2013-01-01

    A recent meta-analysis of 7 genome-wide association studies on early balding (alopecia) revealed single nucleotide polymorphism variants in the region of the amyotrophic lateral sclerosis (ALS) gene TAR DNA-binding protein 43 (TARDBP/TDP-43). We therefore explored the association of early-onset alopecia and ALS in the Health Professionals Follow-up Study, a large cohort of 51,529 US men. In 1992, the participants (then aged 46–81 years) were asked to report their hair line pattern at age 45 years. During the follow-up period (1992–2008), 42 men were diagnosed with ALS. Of those, 13 had reported no alopecia, 18 had reported moderate alopecia, and 11 had reported extensive alopecia at age 45 years. Those who reported extensive alopecia had an almost 3-fold increased risk of ALS compared with those who reported no alopecia (relative risk = 2.74, 95% confidence interval: 1.23, 6.13). Furthermore, we observed a linear trend of increased risk of ALS with increasing level of balding at age 45 years (Ptrend = 0.02). In conclusion, men with early-onset alopecia seem to have a higher risk of ALS. The mechanisms underlying this association deserve further investigation. PMID:23942216

  12. Association between blood lead and the risk of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Fang, Fang; Kwee, Lydia C; Allen, Kelli D; Umbach, David M; Ye, Weimin; Watson, Mary; Keller, Jean; Oddone, Eugene Z; Sandler, Dale P; Schmidt, Silke; Kamel, Freya

    2010-05-15

    The authors conducted a 2003-2007 case-control study including 184 cases and 194 controls to examine the association between blood lead and the risk of amyotrophic lateral sclerosis (ALS) among US veterans and to explore the influence on this association of bone turnover and genetic factors related to lead toxicokinetics. Blood lead, plasma biomarkers of bone formation (procollagen type 1 amino-terminal peptide (PINP)) and resorption (C-terminal telopeptides of type 1 collagen (CTX)), and the K59N polymorphism in the delta-aminolevulinic acid dehydratase gene, ALAD, were measured. Odds ratios and 95% confidence intervals for the association of blood lead with ALS were estimated with unconditional logistic regression after adjustment for age and bone turnover. Blood lead levels were higher among cases compared with controls (P lead was associated with a 1.9-fold increased risk of ALS (95% confidence interval: 1.3, 2.7) after adjustment for age and CTX. Additional adjustment for PINP did not alter the results. Significant lead-ALS associations were observed in substrata of PINP and CTX levels. The K59N polymorphism in the ALAD gene did not modify the lead-ALS association (P = 0.32). These results extend earlier findings by accounting for bone turnover in confirming the association between elevated blood lead level and higher risk of ALS.

  13. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis

    Science.gov (United States)

    Kim, Dohoon; Nguyen, Minh Dang; Dobbin, Matthew M; Fischer, Andre; Sananbenesi, Farahnaz; Rodgers, Joseph T; Delalle, Ivana; Baur, Joseph A; Sui, Guangchao; Armour, Sean M; Puigserver, Pere; Sinclair, David A; Tsai, Li-Huei

    2007-01-01

    A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention. PMID:17581637

  14. Single-photon emission computed tomographic findings and motor neuron signs in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Terao, Shin-ichi; Sobue, Gen; Higashi, Naoki; Takahashi, Masahiko; Suga, Hidemichi; Mitsuma, Terunori

    1995-01-01

    123 I-amphetamine-single photon emission computed tomography (SPECT) was performed on 16 patients with amyotrophic lateral sclerosis (ALS) to investigate the correlation between regional cerebral blood flow (rCBF) and upper motor neuron signs. Significant decreased blood flow less than 2 SDs below the mean of controls was observed in the frontal lobe in 4 patients (25%) and in the frontoparietal lobe including the cortical motor area in 4 patients, respectively. The severity of extermity muscular weakness was significantly correlate with decrease in blood flow through the frontal lobe (p<0.05) and through the frontoparietal lobe (p<0.001). A significant correlation was also noted to exist between the severity of bulbar paralysis and decrease in blood flow through the frontoparietal lobe. No correlation, however, was observed between rCBF and severity of spasticity, presence or absence of Babinski's sign and the duration of illness. Although muscular weakness in the limbs and bulbar paralysis are not pure upper motor neuron signs, the observed reduction in blood flow through the frontal or frontoparietal lobes appears to reflect extensive progression of functional or organic lesions of cortical neurons including the motor area. (author)

  15. Magnetic susceptibility in the deep layers of the primary motor cortex in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Costagli, M; Donatelli, G; Biagi, L; Caldarazzo Ienco, E; Siciliano, G; Tosetti, M; Cosottini, M

    2016-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a progressive neurological disorder that entails degeneration of both upper and lower motor neurons. The primary motor cortex (M1) in patients with upper motor neuron (UMN) impairment is pronouncedly hypointense in Magnetic Resonance (MR) T2* contrast. In the present study, 3D gradient-recalled multi-echo sequences were used on a 7 Tesla MR system to acquire T2*-weighted images targeting M1 at high spatial resolution. MR raw data were used for Quantitative Susceptibility Mapping (QSM). Measures of magnetic susceptibility correlated with the expected concentration of non-heme iron in different regions of the cerebral cortex in healthy subjects. In ALS patients, significant increases in magnetic susceptibility co-localized with the T2* hypointensity observed in the middle and deep layers of M1. The magnetic susceptibility, hence iron concentration, of the deep cortical layers of patients' M1 subregions corresponding to Penfield's areas of the hand and foot in both hemispheres significantly correlated with the clinical scores of UMN impairment of the corresponding limbs. QSM therefore reflects the presence of iron deposits related to neuroinflammatory reaction and cortical microgliosis, and might prove useful in estimating M1 iron concentration, as a possible radiological sign of severe UMN burden in ALS patients.

  16. Exploring sarcasm detection in Amyotrophic Lateral Sclerosis using ecologically valid measures

    Directory of Open Access Journals (Sweden)

    Mathew eStaios

    2013-05-01

    Full Text Available Amyotrophic lateral sclerosis is a rapidly progressive condition involving degeneration of both upper and lower motor neurons. Recent research suggests that a proportion of persons with ALS show a profile similar to that of FTD, with this group of ALS patients exhibiting social cognitive deficits. Although social cognitive deficits have been partially explored in ALS, research has yet to investigate such changes using ecologically valid measures. Therefore, this study aimed to further characterise the scope of social cognitive and emotion recognition deficits in non-demented ALS patients using an ecologically valid measure of social cognition. A sample of 35 ALS patients and 30 age-and-education matched controls were assessed using the Addenbrooke’s Cognitive Examination, the Brixton Spatial Anticipation Test, and The Awareness of Social Inference Test, where participants were required to discriminate between various emotions and decipher socially challenging scenarios enacted in video vignettes. Participants with ALS showed significant difficulties in recognising both sarcastic and paradoxical sarcastic statements, but not sincere statements, when compared to controls. After controlling for executive difficulties, ALS patients still displayed significant difficulties on tasks that assessed their comprehension of both sarcastic and paradoxical sarcastic statements. The inability to read social cues and make social inferences has the potential to place significant strain on familial/interpersonal relationships in ALS. The findings of this study highlight the importance of employing a broader range of neuropsychological assessment tools to aid in early detection of frontal lobe impairment in non-demented ALS patients.

  17. Cannabis and amyotrophic lateral sclerosis: hypothetical and practical applications, and a call for clinical trials.

    Science.gov (United States)

    Carter, Gregory T; Abood, Mary E; Aggarwal, Sunil K; Weiss, Michael D

    2010-08-01

    Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-alpha] inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent would be required to comprehensively address the known pathophysiology of ALS. Remarkably, cannabis appears to have activity in all of those areas. Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. In the G93A-SOD1 ALS mouse, this has translated to prolonged neuronal cell survival, delayed onset, and slower progression of the disease. Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. With respect to the treatment of ALS, from both a disease modifying and symptom management viewpoint, clinical trials with cannabis are the next logical step. Based on the currently available scientific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease.

  18. Clinical attention and assistance profile of patients with amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Núbia Maria Freire Vieira Lima

    2011-04-01

    Full Text Available OBJECTIVE: To evaluate the functional status of amyotrophic lateral sclerosis (ALS patients diagnosed at this institution; to analyze hospital and palliative care; to identify patients' knowledge about home care and supportive resources. METHOD: Twenty-nine patients were evaluated on the ALSFRS-R scale and two semi-structured questionnaires, at the start of the study and every four months thereafter for 1 year. RESULTS: ALSFRS-R score was 30.1±11.5 initially and 24.4±10.5 at 1 year. There was an increase in use of physiotherapeutic care and adaptive aids. The primary caregivers were spouses (55.2%, parents/children/cousins (20.7%, friends (10.3% and private nurses (3.5%; 10.3% of patients had no caregivers. Basic ALS patient care was provided by the public health system. CONCLUSION: ALS patients' multidisciplinary care was provided by UNICAMP hospital and its outpatient clinics and, in some patients, complemented by a private health plan or personal expenditure. Few ALS patients were aware of the possibility of home nursing. It is necessary to implement national and regional public home nursing in addition to multidisciplinary specialized care of ALS patients.

  19. Progressive speech deterioration and dysphagia in amyotrophic lateral sclerosis: case report.

    Science.gov (United States)

    Dworkin, J P; Hartman, D E

    1979-09-01

    Amyotrophic lateral sclerosis (ALS) is a degenerative neurologic disease having both upper and lower motor neuron signs and symptoms. When the speech musculature is involved, a mixed dysarthria and dysphagia usually result. In a 49-year-old man with ALS, dysarthria and dysphagia progressed from mild to severe forms over 17 months. Eleven months after the patient first experienced symptoms, neurologic examination showed fasciculations of the extremities and tongue, limb weakness, and hyperreflexia of the limbs and velopharyngeal mechanism. Tongue strength was one-fourth that of normal. Lingual alternate motions rates for consonant-vowel syllables were also reduced. To enhance lingual strength and swallowing, a tongue-strengthening program was developed for use with articulation training; to augment velopharyngeal function, a palatal lift was fitted; and to increase extremity strength, physical therapy was initiated. Six months after the initial neurologic examination, medical and speech reevaluation showed progressive weakness of the body parts affected initially; continued decline in tongue strength and lingual alternate motion rate; hypoactive reflex activity, indicative of progressive involvement of the lower motor neuron system; and continued deterioration of articulation and phonation owing to the progressive nature of the disease.

  20. Digital cineradiographic study of swallowing in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Lo Re, G; Galia, M; La Grutta, L; Russo, S; Runza, G; Taibbi, A; D'Agostino, T; Lo Greco, V; Bartolotta, T V; Midiri, M; Cardinale, A E; De Maria, M; Lagalla, R

    2007-12-01

    This study was performed to evaluate the usefulness of digital cineradiography in detecting swallowing disorders in dysphagic patients affected by amyotrophic lateral sclerosis (ALS) with a view to planning an adequate therapeutic approach. From January 2005 to September 2006, 23 patients (10 men and 13 women; mean age 41.3+/-8.6 years) affected by ALS were evaluated with digital cineradiography to assess the grade of dysphagia. All patients were classified using the Hillel ALS Severity Scale (ALSSS). All examinations were performed with radiocontrolled equipment provided with a digital C-arm. The cineradiographic technique enabled us to differentiate patients with disorders of the oral (17/23) and/or pharyngeal (19/23) swallowing phase from those without swallowing dysfunction (4/23). In 14/23 patients, passage of contrast medium into the upper airways was observed during swallowing, whereas in 5/23 cases, aspiration of contrast medium into the lower airways was recorded. The videofluoroscopic swallowing study has high diagnostic capabilities in the evaluation of swallowing disorders, as it is able to identify the degree and causes of impairment. In addition, the study proved useful for planning speech therapy and for follow-up in patients with ALS.

  1. Search for compensation postures with videofluoromanometric investigation in dysphagic patients affected by amyotrophic lateral sclerosis.

    Science.gov (United States)

    Solazzo, A; Del Vecchio, L; Reginelli, A; Monaco, L; Sagnelli, A; Monsorrò, M; Di Martino, N; Tedeschi, G; Grassi, R

    2011-10-01

    This study was undertaken to verify the effectiveness of compensatory postures, suggested on the basis of the type of dysphagia identified at videofluoromanometric (VFM) investigation to ensure safe oropharyngeal transit. Eighty-one patients with amyotrophic lateral sclerosis (ALS) underwent speech therapy assessment and VFM investigation of the swallowing process. In the event of altered transit, penetration or aspiration of contrast material into the airways, compensation postures for correction of the swallowing disorder were suggested and verified during VFM examination. In 37 patients, contrast agent transport was preserved and safe; in 19, we observed penetration of the contrast agent into the laryngeal inlet without aspiration; in 24, there was aspiration (four preswallowing, eight intraswallowing, nine postswallowing, three mixed), whereas in one patient no transit was seen. Penetration without aspiration was resolved by coughing or throat clearing; aspiration was resolved in 13 patients by assuming the chin-tuck posture and in six by rotating the head; in five patients, it was not resolved. A hyperextended head posture proved to be effective to resolve lack of transit. By correlating morphological with functional data, VFM enables one not only to precisely characterise the dysphagic disorder but also to identify the most appropriate compensation posture for each patient and verify its effectiveness.

  2. Advances in cellular models to explore the pathophysiology of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Veyrat-Durebex, C; Corcia, P; Dangoumau, A; Laumonnier, F; Piver, E; Gordon, P H; Andres, C R; Vourc'h, P; Blasco, H

    2014-04-01

    Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, is fatal for most patients less than 3 years from when the first symptoms appear. The aetiologies for sporadic and most familial forms of ALS are unknown, but genetic factors are increasingly recognized as causal in a subset of patients. Studies of disease physiology suggest roles for oxidative stress, glutamate-mediated excitotoxicity or protein aggregation; how these pathways interact in the complex pathophysiology of ALS awaits elucidation. Cellular models are being used to examine disease mechanisms. Recent advances include the availability of expanded cell types, from neuronal or glial cell culture to motoneuron-astrocyte co-culture genetically or environmentally modified. Cell culture experiments confirmed the central role of glial cells in ALS. The recent adaptation of induced pluripotent stem cells (iPSC) for ALS modeling could allow a broader perspective and is expected to generate new hypotheses, related particularly to mechanisms underlying genetic factors. Cellular models have provided meaningful advances in the understanding of ALS, but, to date, complete characterization of in vitro models is only partially described. Consensus on methodological approaches, strategies for validation and techniques that allow rapid adaptation to new genetic or environmental influences is needed. In this article, we review the principal cellular models being employed in ALS and highlight their contribution to the understanding of disease mechanisms. We conclude with recommendations on means to enhance the robustness and generalizability of the different concepts for experimental ALS.

  3. Altered cortical hubs in functional brain networks in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Ma, Xujing; Zhang, Jiuquan; Zhang, Youxue; Chen, Heng; Li, Rong; Wang, Jian; Chen, Huafu

    2015-11-01

    Cortical hubs are highly connected nodes in functional brain networks that play vital roles in the efficient transfer of information across brain regions. Although altered functional connectivity has been found in amyotrophic lateral sclerosis (ALS), the changing pattern in functional network hubs in ALS remains unknown. In this study, we applied a voxel-wise method to investigate the changing pattern of cortical hubs in ALS. Through resting-state fMRI, we constructed whole-brain voxel-wise functional networks by measuring the temporal correlations of each pair of brain voxels and identified hubs using the graph theory method. Specifically, a functional connectivity strength (FCS) map was derived from the data on 20 patients with ALS and 20 healthy controls. The brain regions with high FCS values were regarded as functional network hubs. Functional hubs were found mainly in the bilateral precuneus, parietal cortex, medial prefrontal cortex, and in several visual regions and temporal areas in both groups. Within the hub regions, the ALS patients exhibited higher FCS in the prefrontal cortex compared with the healthy controls. The FCS value in the significantly abnormal hub regions was correlated with clinical variables. Results indicated the presence of altered cortical hubs in the ALS patients and could therefore shed light on the pathophysiology mechanisms underlying ALS.

  4. Does dysfunction of the mirror neuron system contribute to symptoms in amyotrophic lateral sclerosis?

    Science.gov (United States)

    Eisen, Andrew; Lemon, Roger; Kiernan, Matthew C; Hornberger, Michael; Turner, Martin R

    2015-07-01

    There is growing evidence that mirror neurons, initially discovered over two decades ago in the monkey, are present in the human brain. In the monkey, mirror neurons characteristically fire not only when it is performing an action, such as grasping an object, but also when observing a similar action performed by another agent (human or monkey). In this review we discuss the origin, cortical distribution and possible functions of mirror neurons as a background to exploring their potential relevance in amyotrophic lateral sclerosis (ALS). We have recently proposed that ALS (and the related condition of frontotemporal dementia) may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. This can include loss of the direct projections from the corticospinal tract, and this is at least part of the explanation for impaired motor control in ALS. Since, in the monkey, corticospinal neurons also show mirror properties, ALS in humans might also affect the mirror neuron system. We speculate that a defective mirror neuron system might contribute to other ALS deficits affecting motor imagery, gesture, language and empathy. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  5. Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

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    Asako Otomo

    2012-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a heterogeneous group of incurable motor neuron diseases (MNDs characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

  6. FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

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    Cao Huang

    2011-03-01

    Full Text Available Fused in Sarcoma (FUS proteinopathy is a feature of frontotemporal lobar dementia (FTLD, and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS. To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution, but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and glial reaction. While transgenic rats that overexpressed the wild-type human FUS were asymptomatic at young ages, they showed a deficit in spatial learning and memory and a significant loss of cortical and hippocampal neurons at advanced ages. These results suggest that mutant FUS is more toxic to neurons than normal FUS and that increased expression of normal FUS is sufficient to induce neuron death. Our FUS transgenic rats reproduced some phenotypes of ALS and FTLD and will provide a useful model for mechanistic studies of FUS-related diseases.

  7. A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

    Science.gov (United States)

    Liu, Anli; Werner, Kelly; Roy, Subhojit; Trojanowski, John Q; Morgan-Kane, Ursula; Miller, Bruce L; Rankin, Katherine P

    2009-06-01

    Patients presenting with left-sided FTLD syndromes sometimes develop a new preoccupation with art, greater attention to visual stimuli, and increased visual creativity. We describe the case of a 53-year-old, right-handed man with a history of bipolar disorder who presented with language and behavior impairments characteristic of FTLD, then developed motor symptoms consistent with a second diagnosis of amyotrophic lateral sclerosis. Though the patient had never created visual art before, he developed a compulsion for painting beginning at the earliest stages of his disease, and continued producing art daily until he could no longer lift a paintbrush because of his motor deficits. Upon autopsy, he was found to have ubiquitin and TDP43-positive inclusions with MND pathology. This case study details the patient's longitudinal neuropsychological, emotional, behavioral, and motor symptoms, along with structural imaging, neurologic, and neuropathologic findings. Multiple examples of the patient's art are depicted throughout all stages of his illness, and the possible cognitive, behavioral, and neurologic correlates of his new-onset visual artistry are discussed.

  8. The follow-up study on patients of Amyotrophic lateral sclerosis

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    Song Bong-kuen

    2010-03-01

    Full Text Available Objectives : This study was to investigate the effects of Oriental medical treatment on ALS. Methods : We investigated 12 ALS patients which were admitted to Gwang-Ju O.M.hospital for 3 months and follow-up at 8 months after discharge. All patients were treated by SAAM-acupuncture, herb medication, Bee venom Pharmacopuncture therapy, Needle-embedding therapy, etc and after discharge self-therapy at home. We evaluated patients using the Amyotrophic lateral sclerosis Functional Rating Scale-Revised(ALSFRS-R, Medical Research Council (MRC Scale. Results : After 1 month, mean ALSFRS-R score of patients was 29.08±7.99, 2 months 28.70±7.17, 3months 28.16±8.23, 1 year 21.33±9.93 and mean MRC Scale of patients was 25.34±8.45, 2 months 25.34±8.45, 3months 21.56±9.20. But in both cases, the variation was not statistically significant. Conclusions : We think that the results of this case be a pilot study that proves the effect of Oriental Medical treatment on ALS.

  9. Magnetic susceptibility in the deep layers of the primary motor cortex in Amyotrophic Lateral Sclerosis

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    M. Costagli

    2016-01-01

    Full Text Available Amyotrophic Lateral Sclerosis (ALS is a progressive neurological disorder that entails degeneration of both upper and lower motor neurons. The primary motor cortex (M1 in patients with upper motor neuron (UMN impairment is pronouncedly hypointense in Magnetic Resonance (MR T2* contrast. In the present study, 3D gradient-recalled multi-echo sequences were used on a 7 Tesla MR system to acquire T2*-weighted images targeting M1 at high spatial resolution. MR raw data were used for Quantitative Susceptibility Mapping (QSM. Measures of magnetic susceptibility correlated with the expected concentration of non-heme iron in different regions of the cerebral cortex in healthy subjects. In ALS patients, significant increases in magnetic susceptibility co-localized with the T2* hypointensity observed in the middle and deep layers of M1. The magnetic susceptibility, hence iron concentration, of the deep cortical layers of patients' M1 subregions corresponding to Penfield's areas of the hand and foot in both hemispheres significantly correlated with the clinical scores of UMN impairment of the corresponding limbs. QSM therefore reflects the presence of iron deposits related to neuroinflammatory reaction and cortical microgliosis, and might prove useful in estimating M1 iron concentration, as a possible radiological sign of severe UMN burden in ALS patients.

  10. Predicting Speech Intelligibility Decline in Amyotrophic Lateral Sclerosis Based on the Deterioration of Individual Speech Subsystems.

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    Rong, Panying; Yunusova, Yana; Wang, Jun; Zinman, Lorne; Pattee, Gary L; Berry, James D; Perry, Bridget; Green, Jordan R

    2016-01-01

    To determine the mechanisms of speech intelligibility impairment due to neurologic impairments, intelligibility decline was modeled as a function of co-occurring changes in the articulatory, resonatory, phonatory, and respiratory subsystems. Sixty-six individuals diagnosed with amyotrophic lateral sclerosis (ALS) were studied longitudinally. The disease-related changes in articulatory, resonatory, phonatory, and respiratory subsystems were quantified using multiple instrumental measures, which were subjected to a principal component analysis and mixed effects models to derive a set of speech subsystem predictors. A stepwise approach was used to select the best set of subsystem predictors to model the overall decline in intelligibility. Intelligibility was modeled as a function of five predictors that corresponded to velocities of lip and jaw movements (articulatory), number of syllable repetitions in the alternating motion rate task (articulatory), nasal airflow (resonatory), maximum fundamental frequency (phonatory), and speech pauses (respiratory). The model accounted for 95.6% of the variance in intelligibility, among which the articulatory predictors showed the most substantial independent contribution (57.7%). Articulatory impairments characterized by reduced velocities of lip and jaw movements and resonatory impairments characterized by increased nasal airflow served as the subsystem predictors of the longitudinal decline of speech intelligibility in ALS. Declines in maximum performance tasks such as the alternating motion rate preceded declines in intelligibility, thus serving as early predictors of bulbar dysfunction. Following the rapid decline in speech intelligibility, a precipitous decline in maximum performance tasks subsequently occurred.

  11. A(aLS: Ammonia-induced amyotrophic lateral sclerosis [version 1; referees: 2 approved

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    Bhavin Parekh

    2015-05-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a dreadful, devastating and incurable motor neuron disease. Aetiologically, it is a multigenic, multifactorial and multiorgan disease. Despite intense research, ALS pathology remains unexplained. Following extensive literature review, this paper posits a new integrative explanation. This framework proposes that ammonia neurotoxicity is a main player in ALS pathogenesis. According to this explanation, a combination of impaired ammonia removal— mainly because of impaired hepatic urea cycle dysfunction—and increased ammoniagenesis— mainly because of impaired glycolytic metabolism in fast twitch skeletal muscle—causes chronic hyperammonia in ALS. In the absence of neuroprotective calcium binding proteins (calbindin, calreticulin and parvalbumin, elevated ammonia—a neurotoxin—damages motor neurons. Ammonia-induced motor neuron damage occurs through multiple mechanisms such as macroautophagy-endolysosomal impairment, endoplasmic reticulum (ER stress, CDK5 activation, oxidative/nitrosative stress, neuronal hyperexcitability and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins’ loss, owing to either ER stress and/or impaired oxidative metabolism, determines clinical variability of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington’s disease and Parkinsonism.

  12. New perspectives on amyotrophic lateral sclerosis: the role of glial cells at the neuromuscular junction.

    Science.gov (United States)

    Arbour, Danielle; Vande Velde, Christine; Robitaille, Richard

    2017-02-01

    Amyotrophic lateral sclerosis (ALS) is a disease leading to the death of motor neurons (MNs). It is also recognized as a non-cell autonomous disease where glial cells in the CNS are involved in its pathogenesis and progression. However, although denervation of neuromuscular junctions (NMJs) represents an early and major event in ALS, the importance of glial cells at this synapse receives little attention. An interesting possibility is that altered relationships between glial cells and MNs in the spinal cord in ALS may also take place at the NMJ. Perisynaptic Schwann cells (PSCs), which are glial cells at the NMJ, show great morphological and functional adaptability to ensure NMJ stability, maintenance and repair. More specifically, PSCs change their properties according to the state of innervation. Hence, abnormal changes or lack of changes can have detrimental effects on NMJs in ALS. This review will provide an overview of known and hypothesized interactions between MN nerve terminals and PSCs at NMJs during development, aging and ALS-induced denervation. These neuron-PSC interactions may be crucial to the understanding of how degenerative changes begin and progress at NMJs in ALS, and represent a novel therapeutic target. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

  13. Clinical utility of FDG-PET in amyotrophic lateral sclerosis and Huntington's disease.

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    Agosta, Federica; Altomare, Daniele; Festari, Cristina; Orini, Stefania; Gandolfo, Federica; Boccardi, Marina; Arbizu, Javier; Bouwman, Femke; Drzezga, Alexander; Nestor, Peter; Nobili, Flavio; Walker, Zuzana; Pagani, Marco

    2018-05-01

    To evaluate the incremental value of FDG-PET over clinical tests in: (i) diagnosis of amyotrophic lateral sclerosis (ALS); (ii) picking early signs of neurodegeneration in patients with a genetic risk of Huntington's disease (HD); and detecting metabolic changes related to cognitive impairment in (iii) ALS and (iv) HD patients. Four comprehensive literature searches were conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on these four diagnostic scenarios. The availability of evidence was good for FDG-PET utility to support the diagnosis of ALS, poor for identifying presymptomatic subjects carrying HD mutation who will convert to HD, and lacking for identifying cognitive-related metabolic changes in both ALS and HD. After the Delphi consensual procedure, the panel did not support the clinical use of FDG-PET for any of the four scenarios. Relative to other neurodegenerative diseases, the clinical use of FDG-PET in ALS and HD is still in its infancy. Once validated by disease-control studies, FDG-PET might represent a potentially useful biomarker for ALS diagnosis. FDG-PET is presently not justified as a routine investigation to predict conversion to HD, nor to detect evidence of brain dysfunction justifying cognitive decline in ALS and HD.

  14. Computed tomographic findings of skeletal muscles in amyotrophic lateral sclerosis (ALS)

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    Takahashi, Ryosuke; Imai, Terukuni; Sadashima, Hiromichi; Matsumoto, Sadayuki; Yamamoto, Toru; Kusaka, Hirobumi; Yamasaki, Masahiro; Maya, Kiyomi; Tanabe, Masaya (Kitano Hospital, Osaka (Japan))

    1989-04-01

    We evaluated the Computed Tomographic (CT) findings of skeletal muscles in 12 cases of amyotrophic lateral sclerosis (ALS), 1 case of spinal progressive muscular atrophy (SPMA), and 1 case of Kugelberg-Welander disease. CT examination was performed in the neck, shoulders, abdomen, pelvis, thighs, and lower legs, 15 muscles were selected for evaluation. The following muscles tended to be affected: m. transversospinalis (12 cases were abnormal), m. deltoideus (10), m. subscapularis (10), m. infraspinatus (10), mm. dorsi (12), hamstring muscles (14), m. tibialis anterior (14), and m. triceps surae (14). On the contrary, the following muscles tended to be preserved: m. sternocleidomastoideus (only 7 cases were abnormal), m. psoas major (7), m. gluteus maximus (7), m. rectus femoris (7), m. sartorius (7) and m. gracilis (6). The distribution of the muscles affected showed neither proximal nor distal dominancy. As the disease advanced, however, all the muscles became affected without any severity. CT findings of skeletal muscles in ALS were characterized by muscle atrophy and fat infiltration, which showed a patchy, linear, or moth-eaten appearance. In mildly affected cases, there was muscle atrophy without internal architectual changes. In moderately affected cases, muscle atrophy advanced and internal architectural changes (patchy, linear, and moth-eaten fat infiltration) became evident. In most advanced cases, every muscle showed a ragged appearance because of severe muscle atrophy and internal architectural changes. These findings were well distinguished from those of SPMA, which resembled the CT pattern of primary muscle diseases. (author).

  15. Patients with sporadic and familial amyotrophic lateral sclerosis found value in genetic testing.

    Science.gov (United States)

    Wagner, Karin N; Nagaraja, Haikady N; Allain, Dawn C; Quick, Adam; Kolb, Stephen J; Roggenbuck, Jennifer

    2017-12-20

    Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a genetic disease. There is no consensus, however, as to the role of genetic testing in the care of the ALS patient. We conducted a survey to study patient access, attitudes, and experience with ALS genetic testing among patients enrolled in a US ALS registry. Among 449 survey respondents, 156 (34.7%) were offered testing and 105 of 156 (67.3%) completed testing. The majority of respondents with familial ALS (fALS) (31/45, 68.9%) were offered testing, while a minority of respondents with sporadic ALS (sALS) (111/404, 27.5%) were offered testing (p = .00001). Comparison of mean test experience scores between groups revealed that respondents with fALS were no more likely to report a favorable experience with genetic testing than those with sALS (p = .51). Respondents who saw a genetic counselor did not have significantly different test experience scores, compared to those who did not (p = .14). In addition, no differences in test experience scores were observed between those who received positive or negative genetic test results (p = .98). These data indicate that patients with ALS found value in clinical genetic testing. © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

  16. Clinical Research on Traditional Chinese Medicine compounds and their preparations for Amyotrophic Lateral Sclerosis.

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    Zhu, Jiayi; Shen, Lan; Lin, Xiao; Hong, Yanlong; Feng, Yi

    2017-12-01

    Amyotrophic lateral sclerosis (ALS) is a chronic, fatal neurodegenerative disease which leads to progressive muscle atrophy and paralysis. In order to summarize the characteristics of Traditional Chinese Medicine compounds and their preparations in the prevention and treatment of ALS through analyzing the mechanism, action site, and symptoms according to effective clinical research. We searched ALS, motor neuron disease, chemical drugs, herbal medicine, Chinese medicine, Traditional Chinese Medicine (TCM), and various combinations of these terms in databases including the PudMed, Springer, Ovid, Google, China National Knowledge Infrastructure, and Wanfang databases. It was found that the chemical drugs almost had not sufficient evidence to show their effectiveness in the treatment of ALS, except RILUZOLE. According to the characteristics of clinical symptoms of ALS, Chinese medicine practitioners believe that this disease belongs to the category of "atrophic disease". In clinical research, many Chinese herbal formulas had good clinical efficacies in the treatment of ALS with multiple targets, multiple links, and few side effects. And four kinds of dialectical treatment had been developed based on Clinical data analysis and the use of dialectical therapy: Benefiting the kidney; Declaring the lungs; Enhancing the Qi; and Dredging the meridian. In this review, we provide an overview of chemical drugs and Traditional Chinese Medicine compound and its preparations in therapy of ALS as well as how they may contribute to the ALS pathogenesis, thereby offering some clues for further studies. Copyright © 2017. Published by Elsevier Masson SAS.

  17. MRI of the intracranial corticospinal tracts in amyotrophic and primary lateral sclerosis

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    Peretti-Viton, P.; Brunel, H.; Daniel, C.; Salazard, B.; Salamon, G.; Azulay, J.P.; Trefouret, S.; Pouget, J.; Serratrice, G.; Viton, J.M.; Flori, A.

    1999-01-01

    Our aim was to investigate the corticospinal tracts (CST) in motor neurone disease, using MRI, and to correlate findings with clinical data. We studied 31 patients with amyotrophic (ALS) and eight with primary lateral sclerosis (PLS). The signal from the CST was classified into four grades on T2-weighted images, and compared to T2-weighted images of 37 age-matched control subjects. No abnormalities were seen in the CST on T1-weighted images and were rarely evident on proton-density weighting. Variable high signal in the CST was found on T2-weighted images in 35 patients, and in 29 control subjects. Our grades 0 and 1 were more frequent in control subjects, grades 2 and 3 more frequent in patients. We found no correlation between the high signal and clinical data, including the duration of the illness. We therefore conclude that this technique is neither sensitive nor specific except in grade 3 which is quite specific for ALS. In half the patients we found atrophy of the superior parietal gyrus, which merits further study. (orig.)

  18. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

    2017-06-01

    Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43 Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43 Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

  19. Mindfulness, physical impairment and psychological well-being in people with amyotrophic lateral sclerosis.

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    Pagnini, Francesco; Phillips, Deborah; Bosma, Colin M; Bosma, M Colin; Reece, Andrew; Langer, Ellen

    2015-01-01

    Mindfulness is the process of actively making new distinctions, rather than relying on habitual or automatic categorisations from the past. Mindfulness has been positively associated with physical well-being, better recovery rates from disease or infections, pain reduction and overall quality of life (QOL). Amyotrophic lateral sclerosis (ALS) is a rare, progressive and fatal neurodegenerative disease, clinically characterised by progressively increasing weakness leading to death, usually within five years. There is presently no cure for ALS, and it is considered one of the most genetically and biologically driven illnesses. Thus far, the aims of psychological studies on ALS have focused on understanding patient - and, to a lesser extent, caregiver - QOL and psychological well-being. No previous study has investigated the influence of psychological factors on ALS. A sample of 197 subjects with ALS were recruited and assessed online twice, with a duration of four months between the two assessments. Assessments included measurements of trait mindfulness, physical impairment, QOL, anxiety and depression. The influence of mindfulness as predictor of changes in physical impairments was evaluated with a mixed-effects model. Mindfulness positively influenced the change of physical symptoms. Subjects with higher mindfulness experienced a slower progression of the disease after four months. Moreover, mindfulness at first assessment predicted higher QOL and psychological well-being. The available data indicate that a psychological construct - mindfulness - can attenuate the progress of a disease that is believed to be almost solely biologically driven. The potential implications of these results extend well beyond ALS.

  20. Voxel-based MRI intensitometry reveals extent of cerebral white matter pathology in amyotrophic lateral sclerosis.

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    Viktor Hartung

    Full Text Available Amyotrophic lateral sclerosis (ALS is characterized by progressive loss of upper and lower motor neurons. Advanced MRI techniques such as diffusion tensor imaging have shown great potential in capturing a common white matter pathology. However the sensitivity is variable and diffusion tensor imaging is not yet applicable to the routine clinical environment. Voxel-based morphometry (VBM has revealed grey matter changes in ALS, but the bias-reducing algorithms inherent to traditional VBM are not optimized for the assessment of the white matter changes. We have developed a novel approach to white matter analysis, namely voxel-based intensitometry (VBI. High resolution T1-weighted MRI was acquired at 1.5 Tesla in 30 ALS patients and 37 age-matched healthy controls. VBI analysis at the group level revealed widespread white matter intensity increases in the corticospinal tracts, corpus callosum, sub-central, frontal and occipital white matter tracts and cerebellum. VBI results correlated with disease severity (ALSFRS-R and patterns of cerebral involvement differed between bulbar- and limb-onset. VBI would be easily translatable to the routine clinical environment, and once optimized for individual analysis offers significant biomarker potential in ALS.

  1. Longitudinal assessment of grey matter contraction in amyotrophic lateral sclerosis: A tensor based morphometry study.

    Science.gov (United States)

    Agosta, Federica; Gorno-Tempini, Maria Luisa; Pagani, Elisabetta; Sala, Stefania; Caputo, Domenico; Perini, Michele; Bartolomei, Ilaria; Fruguglietti, Maria Elena; Filippi, Massimo

    2009-06-01

    Our objective was to investigate grey matter (GM) contraction in patients with amyotrophic lateral sclerosis (ALS) using tensor based morphometry (TBM). Using a 1.5 Tesla scanner, T1-weighted MRI scans were obtained at baseline and at follow-up (mean interval, 9 months) from 16 ALS and 10 controls. Standard TBM procedures in Statistical Parametric Mapping (SPM2) were used for image processing and statistical analyses. The frontotemporal cortex and basal ganglia were considered areas of interest, based on pathological studies. Eight patients showed rapid clinical progression of ALS during the follow-up period. Compared to controls, all ALS patients showed progression of GM atrophy in left premotor cortex and right basal ganglia. Patients with rapidly progressing ALS showed GM atrophy changes in a larger motor cortical-subcortical area and in extramotor frontal regions compared to both controls and to non-rapidly progressing cases. Thus, TBM detected longitudinal atrophy changes in the motor network in ALS occurring over less than one year. The faster the clinical progression, the greater was the GM loss in motor and prefrontal areas. Further advances in tracking longitudinal changes in cortical and subcortical regions in ALS may provide an objective marker for monitoring disease progression, and the disease-modifying effect of potential treatments.

  2. No relation between sympathetic outflow to muscles and respiratory function in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Shindo, Kazumasa; Tsuchiya, Mai; Ichinose, Yuta; Onohara, Akiko; Fukumoto, Megumi; Koh, Kishin; Takaki, Ryusuke; Yamashiro, Nobuo; Kobayashi, Fumikazu; Nagasaka, Takamura; Takiyama, Yoshihisa

    2015-11-15

    In amyotrophic lateral sclerosis (ALS), not only impairment of motor neurons but also impairment of the autonomic nervous system has been demonstrated by previous physiological studies. Several investigators have reported a correlation between autonomic dysfunction and respiratory dysfunction in ALS. This study analyzed the relation between parameters of respiratory function and muscle sympathetic nerve activity (MSNA) in a large number of ALS patients. In 50 patients with ALS (mean age (SD): 62.1 (11.7) years), MSNA, heart rate (HR), and blood pressure (BP) were recorded simultaneously. The arterial oxygen content (PaO2), arterial carbon dioxide content (PaCO2), and forced vital capacity expressed as a percentage of the predicted value for healthy controls (%VC) were determined as parameters of respiratory function. There were no significant correlations between MSNA and PaO2, PaCO2, %VC, or the disability score. Analysis of chronological changes in 14 patients examined twice showed that the disability score and PaCO2 were significantly increased, and %VC was significantly more decreased at the second examination compared with the first examination (prespiratory function in ALS patients is not associated with changes of quantitative MSNA parameters, which may suggest that abnormality of the autonomic nervous system is a primary feature of ALS. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Evidence-based evaluation of therapeutic measures for amyotrophic lateral sclerosis

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    JIA Hua

    2012-06-01

    Full Text Available Objective To evaluate the therapeutic efficacy and side effects of various treatments for amyotrophic lateral sclerosis (ALS in order to formulate the best therapeutic regimen. Methods ALS, Riluzole, Gabapentin, Lamotrigine, neurotrophic factor, antioxidant and free radical scavenger gene therapy, neural stem cell treatment, treatment were appointed as retrieval words. MEDLINE, Cochrane Library, Wanfang Database for Scientific Journals in China and Chinese National Knowledge Infrastructure (CNKI for Scientific Journals Database were used for retrieval. Related clinical guidelines, systematic reviews, randomised controlled trials, controlled clinical trials and case-observation studies were collected following the corresponding inclusion criteria and exclusion criteria and evaluated by Jadad Scale to judge the authenticity and reliability of the conclusion. Manual searching was also used. Results After screening, 39 related articals were selected as follow: 4 systematic reviews, 18 randomised controlled trials, 11 controlled clinical trials, and 6 case-observation studies. Twenty-seven articals were of high quality (according to Jadad Scale, 11 with score 4, 13 with score 5, and 3 with score 7, while 12 were of low quality with score 3. According to the evaluation of therapeutic efficacy and side effects of various therapies, it is suggested that: 1 The Riluzole is the only drug approved by American FDA, lacking of more effective treatments. 2 When the patients' condition is not relieved, medicine-combined therapies and symptomatic treatments should be used. Conclusion Evidence-based medicine can provide best clinical evidence on ALS treatment.

  4. Tongue thickness evaluation using ultrasonography can predict swallowing function in amyotrophic lateral sclerosis patients.

    Science.gov (United States)

    Nakamori, Masahiro; Hosomi, Naohisa; Takaki, Sachiko; Oda, Masaya; Hiraoka, Aya; Yoshikawa, Mineka; Matsushima, Hayato; Ochi, Kazuhide; Tsuga, Kazuhiro; Maruyama, Hirofumi; Izumi, Yuishin; Matsumoto, Masayasu

    2016-02-01

    Dysphagia is a critical issue in amyotrophic lateral sclerosis (ALS) patients. An evaluation of swallowing function is important for assessing the risk of aspiration. We investigated the validity of tongue sonography compared with videofluoroscopic examination for ALS patients. We investigated 18 ALS patients. Nine subjects underwent repeated investigations. All of the subjects underwent tongue sonography and videofluoroscopic examination. Additionally, tongue sonography was evaluated in 18 age- and sex-matched healthy volunteers. To determine tongue thickness, we measured the vertical distance from the surface of the mylohyoid muscle to the tongue dorsum using ultrasonography. In the ALS patients, the tongue was significantly thinner than in healthy subjects. Tongue thickness was associated with body mass index and onset type in the ALS patients (p=0.006). Temporal analyses of videofluoroscopy revealed that tongue thickness was associated with oral preparatory and transit time (p=0.032) but not with pharyngeal transit time. Repeated measurement data revealed a decrease in tongue thickness over the course of the measurements (p=0.002). In ALS patients, reduced tongue thickness suggests disease progression and tongue dysfunction. Tongue sonography is a useful modality for the non-invasive and quantitative evaluation of tongue thickness and dysphagia in ALS patients. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  5. Tongue electrical impedance in amyotrophic lateral sclerosis modeled using the finite element method.

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    Pacheck, Adam; Mijailovic, Alex; Yim, Sung; Li, Jia; Green, Jordan R; McIlduff, Courtney E; Rutkove, Seward B

    2016-03-01

    Electrical impedance myography (EIM) of the tongue has demonstrated alterations in patients with amyotrophic lateral sclerosis (ALS) compared to normal subjects. Whether these differences are due to reduced tongue size or diseased-associated alterations in the electrical characteristics of intrinsic tongue muscles is uncertain. We employed computer simulations using the finite element method, inputting data from healthy and ALS mouse muscle, to help answer that question, comparing our modeled results to human data. The models revealed that much of the electrical current flows superficially in the tongue and that tongue thickness only begins to have a major impact on the measured impedance when substantial atrophy is present. Modeled values paralleled the human tongue data. These findings suggest that the observed changes in tongue impedance in ALS are mainly due to alterations in the electrical properties of the tongue and are not a mere consequence of tongue volume loss. Further development of EIM for evaluation of bulbar dysfunction in ALS may provide useful information on drug efficacy and could serve as a biomarker in future clinical trials. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  6. Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Rajan, Thangavelu Soundara; Scionti, Domenico; Diomede, Francesca; Grassi, Gianpaolo; Pollastro, Federica; Piattelli, Adriano; Cocco, Lucio; Bramanti, Placido; Mazzon, Emanuela; Trubiani, Oriana

    2017-04-01

    Research in recent years has extensively investigated the therapeutic efficacy of mesenchymal stromal cells in regenerative medicine for many neurodegenerative diseases at preclinical and clinical stages. However, the success rate of stem cell therapy remains less at translational phase. Lack of relevant animal models that potentially simulate the molecular etiology of human pathological symptoms might be a reason behind such poor clinical outcomes associated with stem cell therapy. Apparently, self-renewal and differentiation ability of mesenchymal stem cells may help to study the early developmental signaling pathways connected with the diseases, such as Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), etc., at in vitro level. Cannabidiol, a non-psychotrophic cannabinoid, has been demonstrated as a potent anti-inflammatory and neuroprotective agent in neurological preclinical models. In the present study, we investigated the modulatory role of cannabidiol on genes associated with ALS using human gingiva-derived mesenchymal stromal cells (hGMSCs) as an in vitro model system. Next generation transcriptomic sequencing analysis demonstrated considerable modifications in the expression of genes connected with ALS pathology, oxidative stress, mitochondrial dysfunction, and excitotoxicity in hGMSCs treated with cannabidiol. Our results suggest the efficacy of cannabidiol to delineate the unknown molecular pathways, which may underlie ALS pathology at an early stage using hGMSCs as a compelling in vitro system. J. Cell. Biochem. 118: 819-828, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. The Balloon-Based Manometry Evaluation of Swallowing in Patients with Amyotrophic Lateral Sclerosis

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    Jerzy Tomik

    2017-03-01

    Full Text Available The aim of the study was to analyse the disturbances of the oro-pharyngeal swallowing phase of dysphagia in amyotrophic lateral sclerosis (ALS patients with the use of specific manometric measurements and to evaluate their plausible association with the duration of the disease. Seventeen patients with ALS were evaluated with manometric examinations of the oral and pharyngeal part of the gastrointestinal tract. Tests were carried out by using the oesophageal balloon-based method with four balloon transducers located 5 cm away from each other. The following manometric parameters were analysed: the base of tongue contraction (BTC and the upper oesophageal sphincter pressure (UESP, and the hypopharyngeal suction pump (HSP as well as the oro-pharyngeal, pharyngeal and hypopharyngeal transit time and average pharyngeal bolus velocity (oropharyngeal transit time (OTT, pharyngeal transit time (PTT, hypopharyngeal transit time (HTT and average pharyngeal bolus velocity (APBV, respectively. Manomatric examinations during swallowing in patients with ALS showed significant weakness of BTC, a decrease of HSP and a decrease of the velocity of bolus transit inside the pharynx which were particularly marked between the first and the third examination. Manometric examinations of the oro-pharyngeal part of the gastrointestinal tract are useful and supportive methods in the analysis of swallowing disturbances in ALS patients.

  8. Economic burden of amyotrophic lateral sclerosis: a Canadian study of out-of-pocket expenses.

    Science.gov (United States)

    Gladman, Matthew; Dharamshi, Celina; Zinman, Lorne

    2014-09-01

    This study quantifies the 'out-of-pocket' expenses incurred by individuals with amyotrophic lateral sclerosis (ALS) and their families, explores cost-driving factors and describes the current state of financial support in a Canadian cohort. We performed structured cost-of-illness interviews with 50 consecutive ALS patients and family members detailing disease-specific factors, direct and indirect costs. Direct costs were divided into 'out-of-pocket' and 'government/non-profit organization (NPO) supported'. Results showed that the average annual direct cost per patient was $32,337, of which $19,574 (61%) was paid for out-of-pocket. The most significant direct cost was disease-related home renovations, which garnered minimal government or NPO support. The costs of mobility aids, medical expenses, and private personal support workers were also substantial. Higher out-of-pocket costs were associated with an ALS Functional Rating Scale gross motor subscore of ≤ 6 (p = 0.03), limb-predominant symptoms (p = 0.04) and > 4 h/week of personal support care (p = 0.005). Annual indirect costs (lost wages) for patients with ALS and family members providing care were $56,821. In conclusion, this study quantified the substantial personal economic impact of ALS as measured by non-reimbursed, out-of-pocket expenses. Mobilization of additional resources for ALS patients and families is required to soften the economic burden of this disabling disease.

  9. The heterogeneity of amyotrophic lateral sclerosis: a possible explanation of treatment failure.

    Science.gov (United States)

    Beghi, Ettore; Mennini, Tiziana; Bendotti, Caterina; Bigini, Paolo; Logroscino, Giancarlo; Chiò, Adriano; Hardiman, Orla; Mitchell, Douglas; Swingler, Robert; Traynor, Bryan J; Al-Chalabi, Ammar

    2007-01-01

    Amyotrophic lateral sclerosis (ALS) is a severe clinical condition characterized by upper and lower motor neuron degeneration for which there is no truly effective treatment. The absence of an effective treatment can be explained in part by the complex and heterogeneous genetic, biochemical, and clinical features of ALS. While ALS accounts for the majority of the motor neuron diseases, the recognition of disease variants and mimic syndromes may lead to further insights into possible causes for the generality of ALS. From a biochemical perspective, the process of motor neuron degeneration is complex and the multifactorial influences and potential biomarkers of ALS have never been assessed in the light of the clinical heterogeneity of ALS. Several genes and environmental influences have been suggested as possible risk factors of ALS. A better understanding of interactions between these risk factors, potential biomarkers and heterogeneous clinical features may lead to more clearly defined pathological profiles among individuals or groups of ALS patients and in turn lead to more focused therapeutic trials.

  10. Muscle gene expression is a marker of amyotrophic lateral sclerosis severity.

    Science.gov (United States)

    Pradat, Pierre-François; Dubourg, Odile; de Tapia, Marc; di Scala, Franck; Dupuis, Luc; Lenglet, Timothee; Bruneteau, Gaëlle; Salachas, François; Lacomblez, Lucette; Corvol, Jean-Christophe; Demougin, Philippe; Primig, Michael; Meininger, Vincent; Loeffler, Jean-Philippe; Gonzalez de Aguilar, Jose-Luis

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset degenerative disease characterized by the loss of upper and lower motor neurons leading to progressive muscle atrophy and paralysis. The lack of molecular markers of the progression of disease is detrimental to clinical practice and therapeutic trials. This study was designed to identify gene expression changes in skeletal muscle that could reliably define the degree of disease severity. Gene expression profiles were obtained from the deltoid muscles of ALS patients and healthy subjects. Changes in differentially expressed genes were compared to the status of deltoid muscle disability, as determined by manual muscle testing, electrophysiology and the degree of myofiber atrophy. Functionally related genes were grouped by annotation analysis, and deltoid muscle injury was predicted using binary tree classifiers. Two sets of 25 and 70 transcripts appeared differentially regulated exclusively in early and advanced states of deltoid muscle impairment, respectively. The expression of another set of 198 transcripts correlated with a composite score of muscle injury combining manual muscle testing and histological examination. From the totality of these expression changes, 155 transcripts distinguished advanced from early deltoid muscle impairment with 80% sensitivity and 100% specificity. Nine of these transcripts, known also to be regulated in ALS mouse and surgically denervated muscle, predicted the advanced disease status with 100% sensitivity and specificity. We provide robust gene expression changes that can be of practical use when monitoring ALS status and the effects of disease-modifying drugs. Copyright © 2011 S. Karger AG, Basel.

  11. Bcl11b: A New Piece to the Complex Puzzle of Amyotrophic Lateral Sclerosis Neuropathogenesis?

    Science.gov (United States)

    Lennon, Matthew J; Jones, Simon P; Lovelace, Michael D; Guillemin, Gilles J; Brew, Bruce J

    2016-02-01

    Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, neurodegenerative disease of the human motor system. The pathogenesis of ALS is a topic of fascinating speculation and experimentation, with theories revolving around intracellular protein inclusions, mitochondrial structural issues, glutamate excitotoxicity and free radical formation. This review explores the rationale for the involvement of a novel protein, B-cell lymphoma/leukaemia 11b (Bcl11b) in ALS. Bcl11b is a multifunctional zinc finger protein transcription factor. It functions as both a transactivator and genetic suppressor, acting both directly, binding to promoter regions, and indirectly, binding to promoter-bound transcription factors. It has essential roles in the differentiation and growth of various cells in the central nervous system, immune system, integumentary system and cardiovascular system, to the extent that Bcl11b knockout mice are incompatible with extra-uterine life. It also has various roles in pathology including the suppression of latent retroviruses, thymic tumourigenesis and neurodegeneration. In particular its functions in neurodevelopment, viral latency and T-cell development suggest potential roles in ALS pathology.

  12. A Novel Missense Mutation of the DDHD1 Gene Associated with Juvenile Amyotrophic Lateral Sclerosis.

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    Wu, Chujun; Fan, Dongsheng

    2016-01-01

    Background: Juvenile amyotrophic lateral sclerosis (jALS) is a rare form of ALS with an onset age of less than 25 years and is frequently thought to be genetic in origin. DDHD1 gene mutations have been reported to be associated with the SPG28 subtype of autosomal recessive HSP but have never been reported in jALS patients. Methods: Gene screens for the causative genes of ALS, HSP and CMT using next-generation sequencing (NGS) technologies were performed on a jALS patient. Sanger sequencing was used to validate identified variants and perform segregation analysis. Results: We identified a novel c.1483A>G (p.Met495Val) homozygous missense mutation of the DDHD1 gene in the jALS patient. All of his parents and young bother were heterozygous for this mutation. The mutation was not found in 800 Chinese control subjects or the database of dbSNP, ExAC and 1000G. Conclusion: The novel c.1483A>G (p.Met495Val) missense mutation of the DDHD1 gene could be a causative mutation of autosomal recessive jALS.

  13. The investigation of genetic and clinical features in Chinese patients with juvenile amyotrophic lateral sclerosis.

    Science.gov (United States)

    Liu, Z-J; Lin, H-X; Liu, G-L; Tao, Q-Q; Ni, W; Xiao, B-G; Wu, Z-Y

    2017-09-01

    Juvenile amyotrophic lateral sclerosis (JALS) occurs at an age of onset below 25 years with a heterogeneous disease onset location, variable progression and survival time. To investigate whether an ALS gene profile could resolve any aspects of clinical symptom heterogeneity, we have used targeted sequencing technology in a cohort of 12 JALS patients of Chinese descent. We detected 5 likely pathogenic mutations, 2 in familial probands and 3 in sporadic patients. One was a known TARDBP mutation (p.G348V) and 4 were FUS frameshift mutations including a known p.Gln519Ilefs*9 mutation and 3 novel mutations, p.Gly515Valfs*14, p.Gly486Profs*30, and p.Arg498Alafs*32. Of the 4 FUS mutations, 2 were able to be confirmed as de novo mutations. The TARDBP mutation carrier showed a classic ALS phenotype. All patients with FUS mutations experienced limb weakness at an early age and developed bulbar symptoms during the disease course. FUS mutations have previously been associated with increased JALS disease progression, however, we found a large range 12 to 84 months in disease survival (mean 58.2 months). Our results justify future screening for variants in FUS as it remains the most frequent genetic determinant of early onset, JALS (found in 30% of our patients). © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. A pilot clinical study on the Traditional Korean Medicine treatment of Amyotrophic lateral sclerosis

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    Kim Sung-chul

    2009-03-01

    Full Text Available Objectives : This study was to investigate the effect of Oriental medical treatment on ALS. Methods : We investigated 12 ALS patients which were admitted to Gwang-Ju O.M. hospital from Oct. 14, 2008 to Nov. 14, 2008. All patients were treated by SAAM-acupuncture, herb medication, Bee venom Pharmacopuncture therapy, Needle-embedding therapy, etc. We evaluated patients using the Amyotrophic lateral sclerosis Functional Rating Scale-Revised(ALSFRS-R, Medical Research Council (MRC Scale. Results : After 30 days, mean ALSFRS-R score of patients was improved from 28.42±7.83 to 29.08 ±7.99, and mean MRC Scale of patients was improved from 24.79±8.37 to 25.34±8.45. But in both cases, the variation was not statistically significant. After 30 days, mean ALSFRS-R score and mean MRC Scale of patients was more improved in subjects with bulbar-onset, onset age: 51-60yrs., disease duration: 24-48mo. And the results showed partially significant difference. Conclusions : We think that the results of this case be a pilot study that proves the effect of Oriental Medical treatment on ALS.

  15. An exploratory study of serum creatinine levels in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Chen, Xueping; Guo, Xiaoyan; Huang, Rui; Zheng, Zhenzhen; Chen, Yongping; Shang, Hui-Fang

    2014-10-01

    The etiology of amyotrophic lateral sclerosis (ALS) remains unknown, but existing data argue for a role of creatinine in ALS pathophysiology. Our aim is to clarify the correlation between serum creatinine and ALS in Chinese population. A total of 512 sporadic ALS (SALS) patients and 501 age- and gender-matched healthy controls were included. Revised ALS Functional Rating Scale (ALS-FRS-R) was used to assess the motor functional status of SALS patients. Survival analysis was performed using Kaplan-Meier method. Serum creatinine levels were significantly lower in SALS patients than in controls (p creatinine levels had a significantly lower presence of ALS compared to those with the lowest quartile (p for trend serum creatinine levels, but underweight patients presented lower levels of serum creatinine. Patients with low serum creatinine levels are more likely to have severe motor impairment and low body mass index (BMI) values. This study demonstrates that SALS patients have lower serum creatinine levels than well-matched controls. Higher levels of serum creatinine are less likely to be associated with the presence of ALS in Chinese populations. Low serum creatinine levels may be related to severe motor impairment in SALS patients, after adjusting the confounding factor-BMI. However, serum creatinine has no deleterious impact on survival in ALS.

  16. Survival and Cause of Death among a Cohort of Confirmed Amyotrophic Lateral Sclerosis Cases

    Science.gov (United States)

    Paulukonis, Susan T.; Roberts, Eric M.; Valle, Jhaqueline P.; Collins, Natalie N.; English, Paul B.; Kaye, Wendy E.

    2015-01-01

    Introduction Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Estimates of survival from disease onset range from 20 to 48 months and have been generated using clinical populations or death records alone. Methods Data on a cohort of ALS cases diagnosed between 2009–2011 were collected as part of the Los Angeles and San Francisco Bay Area Metropolitan ALS Surveillance projects; death records 2009–2013 were linked to these confirmed cases to determine survival post diagnosis and factors associated with survival time. Results There were 618 cases identified and 283 of these died during the follow up time period. Median age at death was 64.3 years, and median survival time post-diagnosis was 2.6 years. Age at diagnosis and year of diagnosis were predictors of survival time in adjusted models; those diagnosed at age 80 or older had shorter survival than those diagnosed at age 50 or younger. Most (92%) had ALS noted as a cause of death. Discussion Survival post-diagnosis may be improved compared with previous reports. Age at diagnosis continues to be the strongest predictor of prognosis; recall case reporting bias may play a role in estimates of survival time. PMID:26172548

  17. Which behaviours? Identifying the most common and burdensome behaviour changes in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Andrews, Sophie Claire; Pavlis, Alexia; Staios, Mathew; Fisher, Fiona

    2017-04-01

    Behaviour change is increasingly recognised as a common feature of amyotrophic lateral sclerosis (ALS), and may be similar to that seen in frontotemporal dementia (FTD). The behaviours most disturbed in ALS, and those that relate most significantly to caregiver burden, however, have not been well established. Forty ALS participants and their caregivers, and 27 age- and gender-matched healthy controls and their relatives, participated in this study. ALS participants were assessed on a disease rating scale, and caregivers and control informants completed the revised version of the Cambridge Behaviour Inventory and a measure of burden. ALS caregivers reported significantly more disturbance than healthy control informants on the functional domains of everyday skills, self-care, and sleep, and in the behavioural domains of mood and motivation. There were no differences between groups in frequency of memory and orientation difficulties, or behaviours characteristic of FTD, such as changes to eating habits or stereotypic and motor behaviour, indicating that the behavioural profile in ALS may differ from FTD. In the ALS group, the domains with the strongest relationship to caregiver burden were everyday skills, motivation and memory, likely because poor motivation, memory dysfunction and difficulties completing activities of daily living require more carer support via direct supervision, prompting or hands on care. Services to support ALS patients and caregivers need to provide targeted interventions for those functional and behavioural changes which are most burdensome in the disease.

  18. Amyotrophic lateral sclerosis in Brazil: Case series and review of the Brazilian literature.

    Science.gov (United States)

    Prado, Laura de Godoy Rousseff; Bicalho, Isabella Carolina Santos; Vidigal-Lopes, Mauro; Ferreira, Carla Juliana Araújo; Mageste Barbosa, Luiz Sérgio; Gomez, Rodrigo Santiago; De Souza, Leonardo Cruz; Teixeira, Antônio Lúcio

    2016-01-01

    Our objective was to systematically analyse the first series of cases of amyotrophic lateral sclerosis (ALS) in Minas Gerais and to review the Brazilian literature about clinical studies in ALS. This was a cross-sectional and descriptive study of a consecutive series of patients with probable or defined sporadic ALS according to the Awaji criteria, followed at two referral centres of Belo Horizonte (South-east Brazil). Patients underwent full clinical assessment. Comparisons of patient subgroups according to disease duration and initial presentation were performed. A systematic review was performed about Brazilian clinical studies in ALS. Results showed that of the 61 enrolled patients the male/female ratio was 1.6:1. The mean age at onset of symptoms was 54.9 years (SD ± 11.4). Mean age at diagnosis was 56.3 years (SD ± 11.1). Regarding the initial form of presentation, 43 cases (70.5%) were spinal, 12 cases (19.7%) were generalized and six cases (9.8%) were bulbar. Eight studies were found in the systematic review. In conclusion, the profile of our sample was similar to other national and international series, except for fewer cases of bulbar ALS in our series. There are few clinical studies of ALS in Brazil. The national data of prevalence and incidence are still uncertain.

  19. Efficacy of hypnosis-based treatment in Amyotrophic Lateral Sclerosis: A pilot study

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    Arianna ePalmieri

    2012-11-01

    Full Text Available Background: Amyotrophic lateral sclerosis (ALS and its devastating neurodegenerative consequences have an inevitably psychological impact on patients and their caregivers: however, although it would be strongly needed, there is a lack of research on the efficacy of psychological intervention. Our aim was to investigate the effect of hypnosis-based intervention on psychological and perceived physical wellbeing in patients and the indirect effect on caregivers. Methods: We recruited 8 ALS volunteers patients as a pilot sample for an hypnosis intervention and self-hypnosis training protocol lasting one month. Anxiety and depression level was measured in patients and caregivers at pre and post treatment phase. Quality of life and perceived physical symptoms changes were also investigated in patients. Results: One month pre-post treatment improvement in depression, anxiety and quality of life was clearly clinically observed and confirmed by psychometric analyses on questionnaire data. Moreover, decreases in physical symptoms such as pain, sleep disorders, emotional lability and fasciculations were reported by our patients. Improvements in caregiver psychological wellbeing, likely as a consequence of patients psychological and perceived physical symptomatology improvement, were also observed. Conclusions: To the best of our knowledge, even if at a preliminary level, this is the first report on efficacy psychological intervention protocol on ALS patients. The findings provide initial support for using hypnosis and self-hypnosis training to manage some ALS physical consequences and mainly to cope its dramatic psychological implications for patients and, indirectly, for their caregivers.

  20. Predicting Speech Intelligibility Decline in Amyotrophic Lateral Sclerosis Based on the Deterioration of Individual Speech Subsystems

    Science.gov (United States)

    Yunusova, Yana; Wang, Jun; Zinman, Lorne; Pattee, Gary L.; Berry, James D.; Perry, Bridget; Green, Jordan R.

    2016-01-01

    Purpose To determine the mechanisms of speech intelligibility impairment due to neurologic impairments, intelligibility decline was modeled as a function of co-occurring changes in the articulatory, resonatory, phonatory, and respiratory subsystems. Method Sixty-six individuals diagnosed with amyotrophic lateral sclerosis (ALS) were studied longitudinally. The disease-related changes in articulatory, resonatory, phonatory, and respiratory subsystems were quantified using multiple instrumental measures, which were subjected to a principal component analysis and mixed effects models to derive a set of speech subsystem predictors. A stepwise approach was used to select the best set of subsystem predictors to model the overall decline in intelligibility. Results Intelligibility was modeled as a function of five predictors that corresponded to velocities of lip and jaw movements (articulatory), number of syllable repetitions in the alternating motion rate task (articulatory), nasal airflow (resonatory), maximum fundamental frequency (phonatory), and speech pauses (respiratory). The model accounted for 95.6% of the variance in intelligibility, among which the articulatory predictors showed the most substantial independent contribution (57.7%). Conclusion Articulatory impairments characterized by reduced velocities of lip and jaw movements and resonatory impairments characterized by increased nasal airflow served as the subsystem predictors of the longitudinal decline of speech intelligibility in ALS. Declines in maximum performance tasks such as the alternating motion rate preceded declines in intelligibility, thus serving as early predictors of bulbar dysfunction. Following the rapid decline in speech intelligibility, a precipitous decline in maximum performance tasks subsequently occurred. PMID:27148967

  1. Ophthalmic Manifestations of Amyotrophic Lateral Sclerosis (An American Ophthalmological Society Thesis).

    Science.gov (United States)

    Volpe, Nicholas J; Simonett, Joseph; Fawzi, Amani A; Siddique, Teepu

    2015-01-01

    To determine if clinical and histopathologic findings were present in the eyes of patients with amyotrophic lateral sclerosis (ALS) and explore correlations to an animal model of ALS. Two patients with ALS were studied histopathologically as well as the retinas of ALS/dementia transgenic mice with dysfunctional ubiquilin2, UBQLN2(P497H). Clinical study 1, an observational, cross-sectional study, was performed using optical coherence tomography (OCT) to obtain and compare mean total macular thickness and average and quadrant specific peripapillary retinal nerve fiber layer (pRNFL) scans from 16 patients with ALS to controls. Correlation analysis was performed to evaluate the association with disease duration. Clinical study 2 consisted of measuring visual acuity, color vision, contrast sensitivity, and quality of life in 12 patients. Histopathologic studies demonstrated intraretinal inclusions in one patient and loss of ganglion cell axons in another. Mouse eyes had intraretinal inclusions in the inner plexiform layers. Total macular volume was thinner in patients compared to controls (Pvision loss specific for ALS was not identified. This study confirms ocular involvement in patients and transgenic animals with ALS/dementia.

  2. Well-being in amyotrophic lateral sclerosis: a pilot experience sampling study.

    Science.gov (United States)

    Real, Ruben G L; Dickhaus, Thorsten; Ludolph, Albert; Hautzinger, Martin; Kübler, Andrea

    2014-01-01

    The aim of this longitudinal study was to identify predictors of instantaneous well-being in patients with amyotrophic lateral sclerosis (ALS). Based on flow theory well-being was expected to be highest when perceived demands and perceived control were in balance, and that thinking about the past would be a risk factor for rumination which would in turn reduce well-being. Using the experience sampling method, data on current activities, associated aspects of perceived demands, control, and well-being were collected from 10 patients with ALS three times a day for two weeks. RESULTS show that perceived control was uniformly and positively associated with well-being, but that demands were only positively associated with well-being when they were perceived as controllable. Mediation analysis confirmed thinking about the past, but not thinking about the future, to be a risk factor for rumination and reduced well-being. Findings extend our knowledge of factors contributing to well-being in ALS as not only perceived control but also perceived demands can contribute to well-being. They further show that a focus on present experiences might contribute to increased well-being.

  3. Well-being in Amyotrophic Lateral Sclerosis: a pilot Experience Sampling Study

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    Ruben Gustav Leonhardt Real

    2014-07-01

    Full Text Available ObjectiveThe aim of this longitudinal study was to identify predictors of instantaneous well-being in patients with amyotrophic lateral sclerosis (ALS. Based on flow theory well-being was expected to be highest when perceived demands and perceived control were in balance, and that thinking about the past would be a risk factor for rumination which would in turn reduce well-being.MethodsUsing the experience sampling method, data on current activities, associated aspects of perceived demands, control, and well-being were collected from 10 patients with ALS three times a day for two weeks.ResultsResults show that perceived control was uniformly and positively associated with well-being, but that demands were only positively associated with well-being when they were perceived as controllable. Mediation analysis confirmed thinking about the past, but not thinking about the future, to be a risk factor for rumination and reduced well-being. DiscussionFindings extend our knowledge of factors contributing to well-being in ALS as not only perceived control but also perceived demands can contribute to well-being. They further show that a focus on present experiences might contribute to increased well-being.

  4. Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Tosolini, Andrew P; Sleigh, James N

    2017-01-01

    Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the where , which , what , and when in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.

  5. Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Andrew P. Tosolini

    2017-12-01

    Full Text Available Spinal muscular atrophy (SMA and amyotrophic lateral sclerosis (ALS are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector be sensibly selected, but considerable thought must be applied to the where, which, what, and when in order to enhance treatment benefit: to where (cell types and tissues must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.

  6. Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: a systematic review.

    Science.gov (United States)

    Sutedja, Nadia A; Veldink, Jan H; Fischer, Kathelijn; Kromhout, Hans; Heederik, Dick; Huisman, Mark H B; Wokke, John H J; van den Berg, Leonard H

    2009-01-01

    Environmental exposure to chemicals and metals may contribute to the risk of sporadic amyotrophic lateral sclerosis (ALS). Two systematic reviews of the literature on these topics performed according to the well-established MOOSE guidelines are presented. Literature cited in MEDLINE, EMBASE, CINAHL, and Cochrane databases (up to March 2007) as well as references of relevant articles were screened for case-control or cohort studies investigating the associations between sporadic ALS and exposure to chemical agents or metals. Methodology of selected studies was appraised according to Armon's classification system for ALS risk factor studies as well as a newly developed classification system for quality of exposure assessment. Seven of the 38 studies concerning exposure to chemicals and three of the 50 studies concerning exposure to metals fulfilled the validity criteria. In two independent studies meeting the validity criteria, a significant association with increased ALS risk was reported for exposure to pesticides. This systematic review demonstrated the difficulty in attaining a high level of evidence due to lack of high quality of methodological and exposure assessment components. Although pesticide exposure was identified as candidate risk factor, more well-designed studies are needed to provide a definitive answer about exogenous factors of ALS.

  7. Performance predictors of brain-computer interfaces in patients with amyotrophic lateral sclerosis

    Science.gov (United States)

    Geronimo, A.; Simmons, Z.; Schiff, S. J.

    2016-04-01

    Objective. Patients with amyotrophic lateral sclerosis (ALS) may benefit from brain-computer interfaces (BCI), but the utility of such devices likely will have to account for the functional, cognitive, and behavioral heterogeneity of this neurodegenerative disorder. Approach. In this study, a heterogeneous group of patients with ALS participated in a study on BCI based on the P300 event related potential and motor-imagery. Results. The presence of cognitive impairment in these patients significantly reduced the quality of the control signals required to use these communication systems, subsequently impairing performance, regardless of progression of physical symptoms. Loss in performance among the cognitively impaired was accompanied by a decrease in the signal-to-noise ratio of task-relevant EEG band power. There was also evidence that behavioral dysfunction negatively affects P300 speller performance. Finally, older participants achieved better performance on the P300 system than the motor-imagery system, indicating a preference of BCI paradigm with age. Significance. These findings highlight the importance of considering the heterogeneity of disease when designing BCI augmentative and alternative communication devices for clinical applications.

  8. EEG functional network topology is associated with disability in patients with amyotrophic lateral sclerosis

    Science.gov (United States)

    Fraschini, Matteo; Demuru, Matteo; Hillebrand, Arjan; Cuccu, Lorenza; Porcu, Silvia; di Stefano, Francesca; Puligheddu, Monica; Floris, Gianluca; Borghero, Giuseppe; Marrosu, Francesco

    2016-12-01

    Amyotrophic Lateral Sclerosis (ALS) is one of the most severe neurodegenerative diseases, which is known to affect upper and lower motor neurons. In contrast to the classical tenet that ALS represents the outcome of extensive and progressive impairment of a fixed set of motor connections, recent neuroimaging findings suggest that the disease spreads along vast non-motor connections. Here, we hypothesised that functional network topology is perturbed in ALS, and that this reorganization is associated with disability. We tested this hypothesis in 21 patients affected by ALS at several stages of impairment using resting-state electroencephalography (EEG) and compared the results to 16 age-matched healthy controls. We estimated functional connectivity using the Phase Lag Index (PLI), and characterized the network topology using the minimum spanning tree (MST). We found a significant difference between groups in terms of MST dissimilarity and MST leaf fraction in the beta band. Moreover, some MST parameters (leaf, hierarchy and kappa) significantly correlated with disability. These findings suggest that the topology of resting-state functional networks in ALS is affected by the disease in relation to disability. EEG network analysis may be of help in monitoring and evaluating the clinical status of ALS patients.

  9. Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Iyer, Abhirami K; Jones, Kathryn J; Sanders, Virginia M; Walker, Chandler L

    2018-02-23

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS. Specifically, two main opposing hypotheses, the dying forward and dying back phenomena, exist to account for NMJ denervation. The former hypothesis proposes that the earliest degeneration occurs at the central MNs and proceeds to the NMJ, whereas in the latter, the peripheral NMJ is the site of precipitating degeneration progressing backwards to the MN cell body. A large body of literature strongly indicates a role for the immune system in disease onset and progression via regulatory involvement at the level of both the central and peripheral nervous systems (CNS and PNS). In this review, we discuss the earliest reported immune responses with an emphasis on newly identified immune players in mutant superoxide dismutase 1 (mSOD1) transgenic mice, the gold standard mouse model for ALS.

  10. Dysregulation of Iron Metabolism in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

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    Satoru Oshiro

    2011-01-01

    Full Text Available Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs. Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress. In Alzheimer's disease (AD and Parkinson's disease (PD, circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS. Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS. We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress. Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs.

  11. Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks

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    Willekens, Stefanie M.A.; Weehaeghe, Donatienne van [University Hospitals Leuven and KU Leuven, Division of Nuclear Medicine, Department of Imaging and Pathology, Leuven (Belgium); Damme, Philip van [University Hospitals Leuven, Department of Neurology, Leuven (Belgium); KU Leuven, Department of Neurosciences, Experimental Neurology, Leuven (Belgium); Leuven Research Institute for Neuroscience and Disease (LIND), Leuven (Belgium); VIB, Vesalius Research Center, Laboratory of Neurobiology, Leuven (Belgium); Laere, Koen van [University Hospitals Leuven and KU Leuven, Division of Nuclear Medicine, Department of Imaging and Pathology, Leuven (Belgium); Leuven Research Institute for Neuroscience and Disease (LIND), Leuven (Belgium)

    2017-03-15

    During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although [{sup 18}F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression. (orig.)

  12. Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria.

    Science.gov (United States)

    Strong, Michael J; Abrahams, Sharon; Goldstein, Laura H; Woolley, Susan; Mclaughlin, Paula; Snowden, Julie; Mioshi, Eneida; Roberts-South, Angie; Benatar, Michael; HortobáGyi, Tibor; Rosenfeld, Jeffrey; Silani, Vincenzo; Ince, Paul G; Turner, Martin R

    2017-05-01

    This article presents the revised consensus criteria for the diagnosis of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS) based on an international research workshop on frontotemporal dementia (FTD) and ALS held in London, Canada in June 2015. Since the publication of the Strong criteria, there have been considerable advances in the understanding of the neuropsychological profile of patients with ALS. Not only is the breadth and depth of neuropsychological findings broader than previously recognised - - including deficits in social cognition and language - but mixed deficits may also occur. Evidence now shows that the neuropsychological deficits in ALS are extremely heterogeneous, affecting over 50% of persons with ALS. When present, these deficits significantly and adversely impact patient survival. It is the recognition of this clinical heterogeneity in association with neuroimaging, genetic and neuropathological advances that has led to the current re-conceptualisation that neuropsychological deficits in ALS fall along a spectrum. These revised consensus criteria expand upon those of 2009 and embrace the concept of the frontotemporal spectrum disorder of ALS (ALS-FTSD).

  13. UBQLN2 mutations are rare in French and French-Canadian amyotrophic lateral sclerosis.

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    Daoud, Hussein; Suhail, Hamid; Szuto, Anna; Camu, William; Salachas, Francois; Meininger, Vincent; Bouchard, Jean-Pierre; Dupré, Nicolas; Dion, Patrick A; Rouleau, Guy A

    2012-09-01

    Mutations in the UBQLN2 gene, which encodes a member of the ubiquitin-like protein family (ubiquilin-2), have been recently identified in patients with dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS with dementia. We report here the sequencing of the UBQLN2 gene in 590 ALS patients of French and French-Canadian ancestry. We identified two novel missense mutations (p.S155N and p.P189T) in two individuals with sporadic ALS. Bioinformatic analysis predicts that these missense mutations affect the normal protein's function. Importantly, these findings further highlight the importance of the proline residues located in the conserved domains of the ubiquilin-2 protein, suggesting that mutations affecting these residues are particularly relevant to the development of ALS. Our findings further support a causative role of the UBQLN2 gene in the pathogenesis of ALS and suggest that UBQLN2 mutations are rare in the French and French-Canadian population. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons

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    Brian J. Wainger

    2014-04-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1, C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1+/+ stem cell line do not display the hyperexcitability phenotype. SOD1A4V/+ ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.

  15. CRISPR/Cas9 Technology as an Emerging Tool for Targeting Amyotrophic Lateral Sclerosis (ALS

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    Ewa Kruminis-Kaszkiel

    2018-03-01

    Full Text Available The clustered regularly interspaced short palindromic repeats (CRISPR/CRISPR-associated protein-9 nuclease (Cas9 is a genome editing tool that has recently caught enormous attention due to its novelty, feasibility, and affordability. This system naturally functions as a defense mechanism in bacteria and has been repurposed as an RNA-guided DNA editing tool. Unlike zinc-finger nucleases (ZFNs and transcription activator-like effector nucleases (TALENs, CRISPR/Cas9 takes advantage of an RNA-guided DNA endonuclease enzyme, Cas9, which is able to generate double-strand breaks (DSBs at specific genomic locations. It triggers cellular endogenous DNA repair pathways, contributing to the generation of desired modifications in the genome. The ability of the system to precisely disrupt DNA sequences has opened up new avenues in our understanding of amyotrophic lateral sclerosis (ALS pathogenesis and the development of new therapeutic approaches. In this review, we discuss the current knowledge of the principles and limitations of the CRISPR/Cas9 system, as well as strategies to improve these limitations. Furthermore, we summarize novel approaches of engaging the CRISPR/Cas9 system in establishing an adequate model of neurodegenerative disease and in the treatment of SOD1-linked forms of ALS. We also highlight possible applications of this system in the therapy of ALS, both the inherited type as well as ALS of sporadic origin.

  16. Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?

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    Kanouchi, Tadashi; Ohkubo, Takuya; Yokota, Takanori

    2012-07-01

    Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt-Jakob disease. The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of 'propagation' is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.

  17. Deciphering spreading mechanisms in amyotrophic lateral sclerosis: clinical evidence and potential molecular processes.

    Science.gov (United States)

    Pradat, Pierre-François; Kabashi, Edor; Desnuelle, Claude

    2015-10-01

    The aim of this review is to refer to recent arguments supporting the existence of specific propagation mechanisms associated with spreading of neuron injury in amyotrophic lateral sclerosis (ALS). Misfolded ALS-linked protein accumulation can induce aggregation of their native equivalent isoforms through a mechanism analogous to the infectious prion proteins initiation and its propagation. Although ALS is clinically heterogeneous, a shared characteristic is the focal onset and the progressive extension to all body regions. Being viewed until now as just summation of the increased number of affected neurons, dispersion is now rather considered as the result of a seeded self-propagating process. A sequential regional spreading pattern is supported by the distribution of TDP-43 aggregates in ALS autopsy cases. Electrophysiology and advanced neuroimaging methods also recently provided some evidence for propagation of lesions both in the brain and spinal cord, more longitudinal studies being still needed. Lesions are supposed to spread cell-to-cell regionally or through connected neuronal pathway. At the molecular level, the prion-like spreading is an emerging mechanism hypothesis, but other machineries such as those that are in charge of dealing with misfolded proteins and secretion of deleterious peptides may be involved in the propagation of neuron loss. Deciphering the mechanisms underlying spreading of ALS symptoms is of crucial importance to better understand this neurodegenerative disease, build new and appropriate animal models and to define novel therapeutic targets.

  18. Onset and spreading patterns of lower motor neuron involvements predict survival in sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Fujimura-Kiyono, Chieko; Kimura, Fumiharu; Ishida, Simon; Nakajima, Hideto; Hosokawa, Takafumi; Sugino, Masakazu; Hanafusa, Toshiaki

    2011-11-01

    To define patterns of spread through the order of lower motor neuron involvement (first, second or third order), relationships between interval or sites of affected areas from onset to involvement of a second region, and prognosis, including 5 year survival, normal preservation of motor function at onset of respiratory symptoms and cumulative occurrence of each region and direction of spread. 150 patients with sporadic amyotrophic lateral sclerosis (ALS) underwent follow-up at 3 month intervals until the appearance of respiratory symptoms. Symptom appearances were determined using the revised version of the ALS Functional Rating Scale. Median survival with combined type onset (two regions simultaneously) was shorter (18 months) than with bulbar onset (26 months, p=0.01). The interval from onset to involvement of the second region correlated significantly with survival, independent of particular combinations. 5 year survival rate was 21% for lower limb onset, 18% for upper limb onset and 16% for bulbar onset. No patient with a rapid spread pattern (two regions within 3 months from onset) survived >5 years. Early manifestations of bulbar symptoms within 1 year were associated with worse survival (pspread longitudinally to adjacent regions. Bulbar function remained preserved in 27%, lower limb function in 10% and upper limb function in 2.7%. The interval between onset and involvement of the second region is an important predictor of survival. The data support the contiguous anatomical propagation of lower motor neuron involvement in sporadic ALS.

  19. Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis

    Science.gov (United States)

    Nakazawa, Seshiru; Oikawa, Daisuke; Ishii, Ryohei; Ayaki, Takashi; Takahashi, Hirotaka; Takeda, Hiroyuki; Ishitani, Ryuichiro; Kamei, Kiyoko; Takeyoshi, Izumi; Kawakami, Hideshi; Iwai, Kazuhiro; Hatada, Izuho; Sawasaki, Tatsuya; Ito, Hidefumi; Nureki, Osamu; Tokunaga, Fuminori

    2016-01-01

    Optineurin (OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-κB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-κB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-α-mediated NF-κB activation is enhanced in OPTN-knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components. Furthermore, OPTN binds caspase 8, and OPTN deficiency accelerates TNF-α-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-κB are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS. PMID:27552911

  20. Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases?

    Science.gov (United States)

    Bradley, Walter G.; Borenstein, Amy R.; Nelson, Lorene M.; Codd, Geoffrey A.; Rosen, Barry H.; Stommel, Elijah W.; Cox, Paul Alan

    2013-01-01

    There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS) is caused by gene-environment interactions. Mutations in genes underlying familial ALS (fALS) have been discovered in only 5–10% of the total population of ALS patients. Relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron death leading to the syndrome of ALS, although exposure to chemicals including lead and pesticides, and to agricultural environments, smoking, certain sports, and trauma have all been identified with an increased risk of ALS. There is a need for research to quantify the relative roles of each of the identified risk factors for ALS. Recent evidence has strengthened the theory that chronic environmental exposure to the neurotoxic amino acid β-N-methylamino-L-alanine (BMAA) produced by cyanobacteria may be an environmental risk factor for ALS. Here we describe methods that may be used to assess exposure to cyanobacteria, and hence potentially to BMAA, namely an epidemiologic questionnaire and direct and indirect methods for estimating the cyanobacterial load in ecosystems. Rigorous epidemiologic studies could determine the risks associated with exposure to cyanobacteria, and if combined with genetic analysis of ALS cases and controls could reveal etiologically important gene-environment interactions in genetically vulnerable individuals.

  1. Uptake of inorganic mercury by human locus ceruleus and corticomotor neurons: implications for amyotrophic lateral sclerosis

    Science.gov (United States)

    2013-01-01

    Background Environmental toxins are suspected to play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). In an attempt to determine which pathways these toxins can use to enter motor neurons we compared the distribution of mercury in the CNS of a human and of mice that had been exposed to inorganic mercury. Results In the human who had been exposed to metallic mercury, mercury was seen predominantly in the locus ceruleus and corticomotor neurons, as well as in scattered glial cells. In mice that had been exposed to mercury vapor or mercuric chloride, mercury was present in lower motor neurons in the spinal cord and brain stem. Conclusions In humans, inorganic mercury can be taken up predominantly by corticomotor neurons, possibly when the locus ceruleus is upregulated by stress. This toxin uptake into corticomotor neurons is in accord with the hypothesis that ALS originates in these upper motor neurons. In mice, inorganic mercury is taken up predominantly by lower motor neurons. The routes toxins use to enter motor neurons depends on the nature of the toxin, the duration of exposure, and possibly the amount of stress (for upper motor neuron uptake) and exercise (for lower motor neuron uptake) at the time of toxin exposure. PMID:24252585

  2. Molecular Mechanisms in Amyotrophic Lateral Sclerosis: The Role of Angiogenin, a Secreted RNase

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    Isabela M. Aparicio-Erriu

    2012-11-01

    Full Text Available Amyotrophic lateral sclerosis is a fatal neurodegenerative disease caused by the loss of motoneurons. The precise molecular and cellular basis for neuronal death is not yet well established, but the contemporary view is that it is a culmination of multiple aberrant biological processes. Among the proposed mechanisms of motoneuron degeneration, alterations in the homeostasis of RNA binding proteins (RBP and the consequent changes in RNA metabolism have received attention recently.The ribonuclease, angiogenin was one of the first RBPs associated with familial and sporadic ALS. It is enriched in motoneurons under physiological conditions, and is required for motoneuron survival under stress conditions. Furthermore, delivery of angiogenin protects cultured motoneurons against stress-induced injury, and significantly increases the survival of motoneurons in SODG93A mice. In this overview on the role of angiogenin in RNA metabolism and in the control of motoneuron survival, we discuss potential pathogenic mechanisms of angiogenin dysfunction relevant to ALS and other neurodegenerative disorders. We also discuss recent evidence demonstrating that angiogenin secreted from stressed motoneurons may alter RNA metabolism in astrocytes.

  3. Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Tesla, Rachel; Wolf, Hamilton Parker; Xu, Pin; Drawbridge, Jordan; Estill, Sandi Jo; Huntington, Paula; McDaniel, Latisha; Knobbe, Whitney; Burket, Aaron; Tran, Stephanie; Starwalt, Ruth; Morlock, Lorraine; Naidoo, Jacinth; Williams, Noelle S; Ready, Joseph M; McKnight, Steven L; Pieper, Andrew A

    2012-10-16

    We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the hippocampal dentate gyrus. We have further found that chemicals having efficacy in this in vivo screening assay also protect dopaminergic neurons of the substantia nigra following exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a mouse model of Parkinson disease. Here, we provide evidence that an active analog of P7C3, known as P7C3A20, protects ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of amyotrophic lateral sclerosis (ALS). P7C3A20 is efficacious in this model when administered at disease onset, and protection from cell death correlates with preservation of motor function in assays of walking gait and in the accelerating rotarod test. The prototypical member of this series, P7C3, delays disease progression in G93A-SOD1 mice when administration is initiated substantially earlier than the expected time of symptom onset. Dimebon, an antihistaminergic drug with significantly weaker proneurogenic and neuroprotective efficacy than P7C3, confers no protection in this ALS model. We propose that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS.

  4. Association Between Blood Lead and the Risk of Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Fang, Fang; Kwee, Lydia C.; Allen, Kelli D.; Umbach, David M.; Ye, Weimin; Watson, Mary; Keller, Jean; Oddone, Eugene Z.; Sandler, Dale P.; Schmidt, Silke; Kamel, Freya

    2010-01-01

    The authors conducted a 2003–2007 case-control study including 184 cases and 194 controls to examine the association between blood lead and the risk of amyotrophic lateral sclerosis (ALS) among US veterans and to explore the influence on this association of bone turnover and genetic factors related to lead toxicokinetics. Blood lead, plasma biomarkers of bone formation (procollagen type 1 amino-terminal peptide (PINP)) and resorption (C-terminal telopeptides of type 1 collagen (CTX)), and the K59N polymorphism in the δ-aminolevulinic acid dehydratase gene, ALAD, were measured. Odds ratios and 95% confidence intervals for the association of blood lead with ALS were estimated with unconditional logistic regression after adjustment for age and bone turnover. Blood lead levels were higher among cases compared with controls (P < 0.0001, age adjusted). A doubling of blood lead was associated with a 1.9-fold increased risk of ALS (95% confidence interval: 1.3, 2.7) after adjustment for age and CTX. Additional adjustment for PINP did not alter the results. Significant lead-ALS associations were observed in substrata of PINP and CTX levels. The K59N polymorphism in the ALAD gene did not modify the lead-ALS association (P = 0.32). These results extend earlier findings by accounting for bone turnover in confirming the association between elevated blood lead level and higher risk of ALS. PMID:20406759

  5. Efficacy of Hypnosis-Based Treatment in Amyotrophic Lateral Sclerosis: A Pilot Study

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    Palmieri, Arianna; Kleinbub, Johann Roland; Calvo, Vincenzo; Sorarù, Gianni; Grasso, Irene; Messina, Irene; Sambin, Marco

    2012-01-01

    Background: Amyotrophic lateral sclerosis (ALS) and its devastating neurodegenerative consequences have an inevitably psychological impact on patients and their caregivers: however, although it would be strongly needed, there is a lack of research on the efficacy of psychological intervention. Our aim was to investigate the effect of hypnosis-based intervention on psychological and perceived physical wellbeing in patients and the indirect effect on caregivers. Methods: We recruited eight ALS volunteers patients as a pilot sample for an hypnosis intervention and self-hypnosis training protocol lasting 1 month. Anxiety and depression level was measured in patients and caregivers at pre and post treatment phase. Quality of life and perceived physical symptoms changes were also investigated in patients. Results: One month pre-post treatment improvement in depression, anxiety, and quality of life was clearly clinically observed and confirmed by psychometric analyses on questionnaire data. Moreover, decreases in physical symptoms such as pain, sleep disorders, emotional lability, and fasciculations were reported by our patients. Improvements in caregiver psychological wellbeing, likely as a consequence of patients psychological and perceived physical symptomatology improvement, were also observed. Conclusion: To the best of our knowledge, even if at a preliminary level, this is the first report on efficacy psychological intervention protocol on ALS patients. The findings provide initial support for using hypnosis and self-hypnosis training to manage some ALS physical consequences and mainly to cope its dramatic psychological implications for patients and, indirectly, for their caregivers. PMID:23162510

  6. A novel missense mutation of the DDHD1 gene associated with juvenile amyotrophic lateral sclerosis

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    Chujun Wu

    2016-12-01

    Full Text Available Background: Juvenile amyotrophic lateral sclerosis (jALS is a rare form of ALS with an onset age of less than 25 years and is frequently thought to be genetic in origin. DDHD1 gene mutations have been reported to be associated with the SPG28 subtype of autosomal recessive HSP but have never been reported in jALS patients.Methods: Gene screens for the causative genes of ALS, HSP and CMT using next-generation sequencing (NGS technologies were performed on a jALS patient. Sanger sequencing was used to validate identified variants and perform segregation analysis.Results: We identified a novel c.1483A>G (p.Met495Val homozygous missense mutation of the DDHD1 gene in the jALS patient. All of his parents and young bother were heterozygous for this mutation. The mutation was not found in 800 Chinese control subjects or the data of dbSNP, ExAC and 1000G.Conclusion: The novel c.1483A>G (p.Met495Val missense mutation of the DDHD1 gene could be a causative mutation of autosomal recessive jALS.

  7. Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα

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    Massimo Tortarolo

    2017-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFα is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFα levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFα toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFα is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFα in ALS in the light of its multisystem nature.

  8. [Acoustic analysis for 21 patients with amyotrophic lateral sclerosis complaining of dysarthria].

    Science.gov (United States)

    Xie, Hua-shun; Ma, Fu-rong; Fan, Dong-sheng; Wang, Li-ping; Yan, Yan; Lu, Pei-quan

    2014-10-18

    To observe the characteristics of acoustic parameters of 21 patients with amyotrophic lateral sclerosis (ALS) complaining of dysarthria and to explore the possibility and clinical value of Multi-Dimensional Voice Program (MDVP) on aseessing the patient's voice. The clinical data and speech intelligibility of each of the 21 patients with ALS complaining of dysarthria were collected. All the 21 patients with ALS and 44 normal subjects were suggested to pronounce the vowel [a:]. The voice samples were collected and analyzed by Multi Dimensional Voice Program. The data were compared to detect the difference between the two groups. Speech intelligibility of 10 in the 21 patients was above 97% including 5 patients whose scores were 100%. It seemed that the speech intelligibility score was not related with the duration of the disease and the on-set part. The values of noise to harmonic ratio (NHR) of both the light and the severe damage to the speech group were higher than those of the control group with significant difference (Pdysarthria. There was more noise composition in the voice of the patients with dysarthria. NHR seemed to be the sensitive and stable parameter. Especially in patients whose speech intelligibility were affected severely, more acoustic parameters were detected with significant difference.

  9. Dysarthria and quality of life in patients with amyotrophic lateral sclerosis

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    Lavoisier Leite Neto

    Full Text Available ABSTRACT Purpose: to analyze the impact of dysarthria on the quality of life in patients with amyotrophic lateral sclerosis. Methods: the study consisted of 32 subjects, divided into two groups (control group and study group who underwent an initial interview for background information, followed by an evaluation based on the Dysarthria Assessment Protocol and completion of quality of life questionnaire "Living with Dysarthria - (LwD". Exploratory data analysis was collected through mean, median, SD, minimum and maximum measures. A comparison was performed between the studied groups and a correlation was carried out between scores. The significance level adopted was 5%. Results: according to the findings, all sub-items analyzed by the dysarthria assessment protocol were statically significant (p <0.001 when comparing the groups. Regarding quality of life, a moderate positive correlation (p = 0.0008; Spearman's coefficient = 0.75202 was observed between the total score of the two protocols used, indicating that the higher the degree of dysarthria, the worse the Quality of Life (QOL of the subject, according to the parameters evaluated. Conclusion: dysarthria affects all speech parameters herein assessed, in varying degrees, negatively impacting communication and quality of life.

  10. The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis

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    Burcin Ikiz

    2015-07-01

    Full Text Available Neurodegenerative phenotypes reflect complex, time-dependent molecular processes whose elucidation may reveal neuronal class-specific therapeutic targets. The current focus in neurodegeneration has been on individual genes and pathways. In contrast, we assembled a genome-wide regulatory model (henceforth, “interactome”, whose unbiased interrogation revealed 23 candidate causal master regulators of neurodegeneration in an in vitro model of amyotrophic lateral sclerosis (ALS, characterized by a loss of spinal motor neurons (MNs. Of these, eight were confirmed as specific MN death drivers in our model of familial ALS, including NF-κB, which has long been considered a pro-survival factor. Through an extensive array of molecular, pharmacological, and biochemical approaches, we have confirmed that neuronal NF-κB drives the degeneration of MNs in both familial and sporadic models of ALS, thus providing proof of principle that regulatory network analysis is a valuable tool for studying cell-specific mechanisms of neurodegeneration.

  11. Predicting Speech Intelligibility Decline in Amyotrophic Lateral Sclerosis Based on the Deterioration of Individual Speech Subsystems.

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    Panying Rong

    Full Text Available To determine the mechanisms of speech intelligibility impairment due to neurologic impairments, intelligibility decline was modeled as a function of co-occurring changes in the articulatory, resonatory, phonatory, and respiratory subsystems.Sixty-six individuals diagnosed with amyotrophic lateral sclerosis (ALS were studied longitudinally. The disease-related changes in articulatory, resonatory, phonatory, and respiratory subsystems were quantified using multiple instrumental measures, which were subjected to a principal component analysis and mixed effects models to derive a set of speech subsystem predictors. A stepwise approach was used to select the best set of subsystem predictors to model the overall decline in intelligibility.Intelligibility was modeled as a function of five predictors that corresponded to velocities of lip and jaw movements (articulatory, number of syllable repetitions in the alternating motion rate task (articulatory, nasal airflow (resonatory, maximum fundamental frequency (phonatory, and speech pauses (respiratory. The model accounted for 95.6% of the variance in intelligibility, among which the articulatory predictors showed the most substantial independent contribution (57.7%.Articulatory impairments characterized by reduced velocities of lip and jaw movements and resonatory impairments characterized by increased nasal airflow served as the subsystem predictors of the longitudinal decline of speech intelligibility in ALS. Declines in maximum performance tasks such as the alternating motion rate preceded declines in intelligibility, thus serving as early predictors of bulbar dysfunction. Following the rapid decline in speech intelligibility, a precipitous decline in maximum performance tasks subsequently occurred.

  12. Rac1 at the crossroad of actin dynamics and neuroinflammation in Amyotrophic Lateral Sclerosis

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    Nadia eD'Ambrosi

    2014-09-01

    Full Text Available Rac1 is a major player of the Rho family of small GTPases that controls multiple cell signaling pathways, such as the organization of cytoskeleton (including adhesion and motility, cell proliferation, apoptosis and activation of immune cells. In the nervous system, in particular, Rac1 GTPase plays a key regulatory function of both actin and microtubule cytoskeletal dynamics and thus it is central to axonal growth and stability, as well as dendrite and spine structural plasticity. Rac1 is also a crucial regulator of NADPH-dependent membrane oxidase (NOX, a prominent source of ROS, thus having a central role in the inflammatory response and neurotoxicity mediated by microglia cells in the nervous system. As such, alterations in Rac1 activity might well be involved in the processes that give rise to Amyotrophic Lateral Sclerosis (ALS, a complex syndrome where cytoskeletal disturbances in motor neurons and redox alterations in the inflammatory compartment play pivotal and synergic roles in the final disease outcomes. Here we will discuss the genetic and mechanistic evidence indicating the relevance of Rac1 dysregulation in the pathogenesis of ALS.

  13. Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

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    Hamideh Shahheydari

    2017-05-01

    Full Text Available Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER-associated degradation (ERAD and the formation of stress granules (SGs, to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials.

  14. Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Zhao, Yanli; Cudkowicz, Merit E; Shefner, Jeremy M; Krivickas, Lisa; David, William S; Vriesendorp, Francine; Pestronk, Alan; Caress, James B; Katz, Jonathan; Simpson, Ericka; Rosenfeld, Jeffrey; Pascuzzi, Robert; Glass, Jonathan; Rezania, Kourosh; Harmatz, Jerold S; Schoenfeld, David; Greenblatt, David J

    2014-10-01

    The cephalosporin antibiotic ceftriaxone was evaluated as a potential therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS). The pharmacokinetics (PK) of ceftriaxone in plasma and cerebrospinal fluid (CSF) were investigated in 66 participants in a previously reported clinical trial. Their mean age was 51 years, and 65% were male. Participants were randomly assigned to 1 of 3 treatment groups receiving intravenous infusions (mean duration: 25 minutes) every 12 hours of either: placebo and placebo; 2 g ceftriaxone and placebo; or 2 g ceftriaxone twice. Mean steady-state plasma PK variables were: volume of distribution, 14 L (0.17 L/kg); elimination half-life, 8-9 h; total clearance, 17-21 mL/min (0.22-0.25 mL/min/kg). Values were not different between dosage groups. CSF PK analysis, determined through sparse CSF sampling, indicated apparent entry and elimination half-life values of 1.0 and 34 hours, respectively. With both dosage regimens, CSF concentrations were maintained above the target threshold of 1.0 µM (0.55 µg/mL) as determined from in vitro models. The plasma and CSF PK profiles of ceftriaxone were used as a basis for planning the Phase 3 clinical trial of ceftriaxone in ALS. © 2014, The American College of Clinical Pharmacology.

  15. Myasthenia gravis with muscle specific kinase antibodies mimicking amyotrophic lateral sclerosis.

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    Huijbers, Maartje G; Niks, Erik H; Klooster, Rinse; de Visser, Marianne; Kuks, Jan B; Veldink, Jan H; Klarenbeek, Pim; Van Damme, Philip; de Baets, Marc H; van der Maarel, Silvère M; van den Berg, Leonard H; Verschuuren, Jan J

    2016-06-01

    Muscle-specific kinase (MuSK) myasthenia gravis (MG) is hallmarked by the predominant involvement of bulbar muscles and muscle atrophy. This might mimic amyotrophic lateral sclerosis (ALS) presenting with bulbar weakness. We encountered four cases of MuSK MG patients with an initial misdiagnosis of ALS. We analyzed the clinical data of the four misdiagnosed MuSK MG patients, and investigated the presence of MuSK autoantibodies in a group of 256 Dutch bulbar-onset ALS patients using a recombinant MuSK ELISA and a standard MuSK radioimmunorecipitation assay. Clues for changing the diagnosis were slow progression, clinical improvement, development of diplopia and absence of signs of upper motor neuron involvement. No cases of MuSK MG were identified among a group of 256 bulbar ALS patients diagnosed according to the revised El Escorial criteria. A misdiagnosis of ALS in patients with MuSK MG is rare. We recommend to carefully consider the diagnosis of MuSK MG in patients presenting with bulbar weakness without clear signs of upper motor neuron dysfunction. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Unusual association of amyotrophic lateral sclerosis and myasthenia gravis: A dysregulation of the adaptive immune system?

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    Del Mar Amador, Maria; Vandenberghe, Nadia; Berhoune, Nawel; Camdessanché, Jean-Philippe; Gronier, Sophie; Delmont, Emilien; Desnuelle, Claude; Cintas, Pascal; Pittion, Sophie; Louis, Sarah; Demeret, Sophie; Lenglet, Timothée; Meininger, Vincent; Salachas, François; Pradat, Pierre-François; Bruneteau, Gaëlle

    2016-06-01

    Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions that has been associated with a small increased risk of amyotrophic lateral sclerosis (ALS). Here, we describe a retrospective series of seven cases with a concomitant diagnosis of ALS and myasthenia gravis, collected among the 18 French reference centers for ALS in a twelve year period. After careful review, only six patients strictly met the diagnostic criteria for both ALS and myasthenia gravis. In these patients, limb onset of ALS was reported in five (83%) cases. Localization of myasthenia gravis initial symptoms was ocular in three (50%) cases, generalized in two (33%) and bulbar in one (17%). Median delay between onset of the two conditions was 19 months (6-319 months). Anti-acetylcholine receptor antibodies testing was positive in all cases. All patients were treated with riluzole and one had an associated immune-mediated disease. In the one last ALS case, the final diagnosis was false-positivity for anti-acetylcholine receptor antibodies. The co-occurrence of ALS and myasthenia gravis is rare and requires strict diagnostic criteria. Its demonstration needs thoughtful interpretation of electrophysiological results and exclusion of false positivity for myasthenia gravis antibody testing in some ALS cases. This association may be triggered by a dysfunction of adaptive immunity. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. [Evaluation and treatment of dysphagia in amyotrophic lateral sclerosis and Parkinson's disease].

    Science.gov (United States)

    Yamamoto, Toshiyuki

    2011-11-01

    As both amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) exhibit a variety of patterns of dysphagia, appropriate symptomatic treatment is provided after evaluation of swallowing function through videofluoroscopic examination of swallowing. In ALS, disease progression is rapid, therefore, respiratory function, swallowing function and nutritional status should be evaluated regularly. When the oral or pharyngeal stage of swallowing are affected early in dysphagia, adjusting swallowing volume and varying consistency can be beneficial in ALS. When all stages of swallowing are impaired in ALS, such complications as pneumonia, dehydration and malnutrition, are observed. In such patients, it is necessary to consider an alternative to oral dietary intake. In PD, dysphagia is not necessarily associated with severity of parkinsonism and can appear at any time during the course of the disease. Dysphagia in PD can occur at any stage of swallowing and frequently accompanies multiple abnormalities. In particular, aspiration is an important risk factor for pneumonia in PD. The effect of L-dopa treatment for dysphagia is often insufficient; however, this treatment remains the first choice because dysphagia is exacerbated during off state. Rehabilitation for dysphagia in PD has also some effect.

  18. [Health-related quality of life in patients with amyotrophic lateral sclerosis].

    Science.gov (United States)

    Sánchez-López, C R; Perestelo-Pérez, L; Ramos-Pérez, C; López-Bastida, J; Serrano-Aguilar, P

    2014-01-01

    Progressive deterioration in patients with amyotrophic lateral sclerosis (ALS) has a major impact on their health-related quality of life (HRQOL). The objectives of this study are to evaluate HRQOL in a sample of patients diagnosed with ALS and estimate the predictive capability of a set of sociodemographic variables for the different scales covered by a general health survey. A total of 63 patients diagnosed with ALS were assessed using a sociodemographic questionnaire and the SF-36 general health survey. The sociodemographic variables studied were sex, age, presence of a caregiver, employment status, and time from diagnosis of disease. The SF-36 survey shows positive correlations between the different scales composing it, which proves its reliability. The mean scores obtained for each of the SF-36 scales were higher in men than in women, although the only statistically significant difference was for the Physical Role scale. The lowest age range (less than 56 years) presented the highest mean scores for most of these dimensions. Most of the variance in the test is explained by the variable 'presence of caregiver'. The SF-36 health survey has been confirmed as a valid and useful tool for evaluating HRQOL in ALS patients, and it discriminates between patients in different states of health according to their level of dependency. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  19. Exposure to hazardous air pollutants and the risk of amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Malek, Angela M.; Barchowsky, Aaron; Bowser, Robert; Heiman-Patterson, Terry; Lacomis, David; Rana, Sandeep; Ada Youk; Talbott, Evelyn O.

    2015-01-01

    Background: Amyotrophic lateral sclerosis (ALS) is a serious and rapidly fatal neurodegenerative disorder with an annual incidence of 1–2.6/100,000 persons. Few known risk factors exist although gene–environment interaction is suspected. We investigated the relationship between suspected neurotoxicant hazardous air pollutants (HAPs) exposure and ALS. Methods: A case–control study involving sporadic ALS cases (n = 51) and matched controls (n = 51) was conducted from 2008 to 2011. Geocoded residential addresses were linked to U.S. EPA NATA data (1999, 2002, and 2005) by census tract. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Results: Residential exposure to aromatic solvents significantly elevated the risk of ALS among cases compared to controls in 2002 (OR = 5.03, 95% CI: 1.29, 19.53) and 1999 (OR = 4.27, 95% CI: 1.09, 16.79) following adjustment for education, smoking, and other exposure groups. Metals, pesticides, and other HAPs were not associated with ALS. Conclusions: A potential relationship is suggested between residential ambient air aromatic solvent exposure and risk of ALS in this study. - Highlights: • The effects of ambient air pollutants and risk of ALS was assessed. • EPA NATA data linked to geocoded addresses for 1999, 2002, and 2005. • Residential exposure to aromatic solvents was associated with an increased risk of ALS. - Residential exposure to aromatic solvents was associated with an increased risk of ALS

  20. Cerebrospinal fluid cytotoxicity does not affect survival in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Galán, L; Matías-Guiu, J; Matias-Guiu, J A; Yáñez, M; Pytel, V; Guerrero-Sola, A; Vela-Souto, A; Arranz-Tagarro, J A; Gómez-Pinedo, U; García, A G

    2017-09-01

    Cerebrospinal fluid (CSF) from some patients with amyotrophic lateral sclerosis (ALS) has been demonstrated to significantly reduce the neuronal viability of primary cell cultures of motor neurons. We aimed to study the potential clinical consequences associated with the cytotoxicity of CSF in a cohort of patients with ALS. We collected CSF from thirty-one patients with ALS. We analysed cytotoxicity by incubating it into the primary cultures of motor cortex neurons. Neural viability was quantified after 24 hours using the colorimetric MTT reduction assay. All patients were followed up from the moment of diagnosis to death, and a complete evaluation during disease progression and survival was performed, including gastrostomy and respiratory assistance. Twenty-one patients (67.7%) presented a cytotoxic CSF. There were no significant differences between patients with and without cytotoxicity regarding mean time from symptom onset to the diagnosis, from the diagnosis to death, from the diagnosis to respiratory assistance with BIPAP, from diagnosis to gastrostomy and from the onset of symptoms to death. In Cox regression analysis, bulbar onset, but not cytotoxicity, gender or age at onset, was associated with a lower risk of survival. Cerebrospinal fluid cytotoxicity was not associated with differential survival rates. This suggests that the presence of cytotoxicity in CSF, measured through neuronal viability in primary cultures of motor cortex neurons, could reflect different mechanisms of the disease, but it does not predict disease outcome. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model.

    Science.gov (United States)

    Lee, Joo-Yong; Kawaguchi, Yoshiharu; Li, Ming; Kapur, Meghan; Choi, Su Jin; Kim, Hak-June; Park, Song-Yi; Zhu, Haining; Yao, Tso-Pang

    2015-01-01

    Aberrant accumulation of protein aggregates is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although a buildup of protein aggregates frequently leads to cell death, whether it is the key pathogenic factor in driving neurodegenerative disease remains controversial. HDAC6, a cytosolic ubiquitin-binding deacetylase, has emerged as an important regulator of ubiquitin-dependent quality control autophagy, a lysosome-dependent degradative system responsible for the disposal of misfolded protein aggregates and damaged organelles. Here, we show that in cell models HDAC6 plays a protective role against multiple disease-associated and aggregation-prone cytosolic proteins by facilitating their degradation. We further show that HDAC6 is required for efficient localization of lysosomes to protein aggregates, indicating that lysosome targeting to autophagic substrates is regulated. Supporting a critical role of HDAC6 in protein aggregate disposal in vivo, genetic ablation of HDAC6 in a transgenic SOD1G93A mouse, a model of ALS, leads to dramatic accumulation of ubiquitinated SOD1G93A protein aggregates. Surprisingly, despite a robust buildup of SOD1G93A aggregates, deletion of HDAC6 only moderately modified the motor phenotypes. These findings indicate that SOD1G93A aggregation is not the only determining factor to drive neurodegeneration in ALS, and that HDAC6 likely modulates neurodegeneration through additional mechanisms beyond protein aggregate clearance. © 2015 S. Karger AG, Basel.

  2. The Emerging Role of the Major Histocompatibility Complex Class I in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Chiarotto, Gabriela Bortolança; Nardo, Giovanni; Trolese, Maria Chiara; França, Marcondes Cavalcante; Bendotti, Caterina; Rodrigues de Oliveira, Alexandre Leite

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motoneurons (MNs). The etiology of the disease is still unknown for most patients with sporadic ALS, while in 5-10% of the familial cases, several gene mutations have been linked to the disease. Mutations in the gene encoding Cu, Zn superoxide dismutase (SOD1), reproducing in animal models a pathological scenario similar to that found in ALS patients, have allowed for the identification of mechanisms relevant to the ALS pathogenesis. Among them, neuroinflammation mediated by glial cells and systemic immune activation play a key role in the progression of the disease, through mechanisms that can be either neuroprotective or neurodetrimental depending on the type of cells and the MN compartment involved. In this review, we will examine and discuss the involvement of major histocompatibility complex class I (MHCI) in ALS concerning its function in the adaptive immunity and its role in modulating the neural plasticity in the central and peripheral nervous system. The evidence indicates that the overexpression of MHCI into MNs protect them from astrocytes' toxicity in the central nervous system (CNS) and promote the removal of degenerating motor axons accelerating collateral reinnervation of muscles.

  3. Clinical recognition and management of amyotrophic lateral sclerosis: the nurse's role.

    Science.gov (United States)

    Clarke, Kathie; Levine, Todd

    2011-08-01

    Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, causes a progressive wasting and loss of the upper and lower motor neurons that facilitate the movement of body parts. At onset, ALS patients may show symptoms such as muscle weakness, atrophy, hyperreflexia, or bulbar symptoms such as dysphagia or dysarthria. Deterioration progresses rapidly, and the later stages of ALS are characterized by severely limited mobility and respiratory failure, which is the primary cause of death. There is no specific diagnostic test for ALS, and there are a number of other conditions that may resemble ALS, making a diagnosis difficult. The variability of the initial presentation combined with the broad differential diagnosis may result in significant delays in diagnosis or, in some cases, misdiagnosis, which in turn have a negative impact on patient outcomes. There is no cure for ALS; however, many of the symptoms are treatable, and the physical and psychological symptoms are best managed through the efforts of a coordinated, multidisciplinary team. Nurses play a critical role in the clinical management of ALS and may be involved in coordinating the activities of the team, facilitating treatment, and helping patients and caregivers in making informed treatment and end-of-life decisions. Drug therapy for ALS is currently limited to riluzole; however, patients may be treated with a number of nonpharmacologic methods on the basis of their symptoms. A number of other treatment modalities, such as stem-cell-based therapy or gene therapy, and an array of neuroprotective clinical trials are currently under development for the treatment of ALS. Nurses may also have a key role in these various ALS studies.

  4. Microstructural changes across different clinical milestones of disease in amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Francesca Trojsi

    Full Text Available Neurodegenerative process in amyotrophic lateral sclerosis (ALS has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS diffusion tensor imaging (DTI and voxel-based morphometry (VBM analyses. We aimed to identify white (WM and gray matter (GM patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions exhibited decreased fractional anisotropy (FA (p<0.001, uncorrected and increased mean (MD and radial diffusivity (RD (p<0.001, uncorrected in the left cerebellar hemisphere and brainstem precerebellar nuclei, as well as in motor areas, while GM atrophy (p<0.001, uncorrected was detected only in the left inferior frontal gyrus and right cuneus. Finally, ALS patients in stage 3 (with impairment of three functional regions exhibited decreased FA and increased MD and RD (p<0.05, corrected within WM underneath bilateral pre and postcentral gyri, corpus callosum midbody, long associative tracts and midbrain, while no significant clusters of GM atrophy were observed. Our findings reinforce the hypothesis that the neurodegenerative process propagates along the axonal pathways and develops beyond motor areas from early stages, involving progressively several frontotemporal regions and their afferents and efferents, while the detection of GM atrophy in earlier stages and its disappearance in later stages may be the result of

  5. Structural hallmarks of amyotrophic lateral sclerosis progression revealed by probabilistic fiber tractography.

    Science.gov (United States)

    Steinbach, Robert; Loewe, Kristian; Kaufmann, Joern; Machts, Judith; Kollewe, Katja; Petri, Susanne; Dengler, Reinhard; Heinze, Hans-Jochen; Vielhaber, Stefan; Schoenfeld, Mircea Ariel; Stoppel, Christian Michael

    2015-10-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive limb and/or bulbar muscular weakness and atrophy. Although ALS-related alterations of motor and extra-motor neuronal networks have repeatedly been reported, their temporal dynamics during disease progression are not well understood. Recently, we reported a decline of motor system activity and a concurrent increase of hippocampal novelty-evoked modulations across 3 months of ALS progression. To address whether these functional changes are associated with structural ones, the current study employed probabilistic fiber tractography on diffusion tensor imaging (DTI) data using a longitudinal design. Therein, motor network integrity was assessed by DTI-based tracking of the intracranial corticospinal tract, while connectivity estimates of occipito-temporal tracts (between visual and entorhinal, perirhinal or parahippocampal cortices) served to assess structural changes that could be related to the increased novelty-evoked hippocampal activity across time described previously. Complementing these previous functional observations, the current data revealed an ALS-related decrease in corticospinal tract structural connectivity compared to controls, while in contrast, visuo-perirhinal connectivity was relatively increased in the patient group. Importantly, beyond these between-group differences, a rise in the patients' occipito-temporal tract strengths occurred across a 3-month interval, while at the same time no changes in corticospinal tract connectivity were observed. In line with previously identified functional alterations, the dynamics of these structural changes suggest that the affection of motor- and memory-related networks in ALS emerges at distinct disease stages: while motor network degeneration starts primarily during early (supposedly pre-symptomatic) phases, the hippocampal/medial temporal lobe dysfunctions arise at later stages of the disease.

  6. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Humala Nelson

    2006-04-01

    Full Text Available Abstract Background The cause of neuronal death in amyotrophic lateral sclerosis (ALS is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization. Results SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD based on known formulations for humans. Motor performance, longevity, and motor neuron counts were measured in treated and disease controls. Because mitochondrial dysfunction plays a central role in neuronal cell death in ALS, we also studied the effect that the principal ketone body, D-β-3 hydroxybutyrate (DBH, has on mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline motor performance 25 days later than disease controls. KD animals weighed 4.6 g more than disease control animals at study endpoint; the interaction between diet and change in weight was significant (p = 0.047. In spinal cord sections obtained at the study endpoint, there were more motor neurons in KD fed animals (p = 0.030. DBH prevented rotenone mediated inhibition of mitochondrial complex I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH. Conclusion This is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain.

  7. Characteristics of sleep dysfunction and sleep - disordered breathing in amyotrophic lateral sclerosis patients

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    Fang WANG

    2017-10-01

    Full Text Available Objective To study the characteristics of sleep architecture and sleep - disordered breathing (SDB in patients with amyotrophic lateral sclerosis (ALS using polysomnography (PSG. Methods A total of 36 patients with ALS were recruited in this study. According to symptoms of medulla oblongata, the patients were divided into limb involvement group (N = 14 and bulbar palsy group (N = 22. Detailed record of the patients was made including general information and chief complaints of sleep dysfunction and SDB, which covered sleep initiation and maintenance disorders, arousals, difficulty in breathing and snoring, nocturnal polyuria, restless legs syndrome (RLS and muscle soreness. Appel Amyotrophic Lateral Sclerosis (AALS Scores were used to assess bulbar function, breathing function,myodynamia and limbs function. PSG was performed to monitor EEG, EOG, EMG, ECG, position, snore, gas flow of mouth and nose, chest breathing, pulse oxygen saturation (SpO2 and sleep-related parameters including total sleep time (TST, sleep efficiency (SE, sleep latency (SL, awakening times, percentage of different non-rapid eye movement (NREM and rapial eye movement (REM, and apnea hypopnea index (AHI. Pearson correlation analysis evaluated the relationship between AHI of REM, periodic limb movements (PLM and clinical information, AALS Scores. Results Bulbar palsy group had higher scores in AALS Scores (P = 0.007, bulbar function (P = 0.000 and breathing function (P = 0.000, and lower score in upper limb myodynamia (P = 0.016 than limb involvement group. Both 2 groups showed disturbed sleep architecture in the performance of sleep fragmentation. Bulbar palsy group had more awakening times (P = 0.027, lower percentage of REM sleep (P = 0.009 and less PLM (P = 0.020 than limb involvement group. The main respiratory event of 2 groups was hypopnea. Bulbar palsy group had higher AHI (P = 0.038 and AHI of REM and NREM (P = 0.031, 0.049 than limb involvement group. Pearson

  8. Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease.

    Science.gov (United States)

    Dal Bello-Haas, Vanina; Florence, Julaine M

    2013-05-31

    Despite the high incidence of muscle weakness in individuals with amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), the effects of exercise in this population are not well understood. This is an update of a review first published in 2008. To systematically review randomised and quasi-randomised studies of exercise for people with ALS or MND. We searched The Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), AMED (January 1985 to June 2012), CINAHL Plus (January 1938 to June 2012), LILACS (January 1982 to June 2012), Ovid HealthSTAR (January 1975 to December 2012). We also searched ProQuest Dissertations & Theses A&I (2007 to 2012), inspected the reference lists of all papers selected for review and contacted authors with expertise in the field. We included randomised or quasi-randomised controlled trials of people with a diagnosis of definite, probable, probable with laboratory support, or possible ALS, as defined by the El Escorial criteria. We included progressive resistance or strengthening exercise, and endurance or aerobic exercise. The control condition was no exercise or standard rehabilitation management. Our primary outcome measure was improvement in functional ability, decrease in disability or reduction in rate of decline as measured by a validated outcome tool at three months. Our secondary outcome measures were improvement in psychological status or quality of life, decrease in fatigue, increase in, or reduction in rate of decline of muscle strength (strengthening or resistance studies), increase in, or reduction in rate of decline of aerobic endurance (aerobic or endurance studies) at three months and frequency of adverse effects. We did not exclude studies on the basis of measurement of outcomes. Two review authors independently assessed trial quality and extracted the data. We collected

  9. Comorbidity of dementia with amyotrophic lateral sclerosis (ALS): insights from a large multicenter Italian cohort.

    Science.gov (United States)

    Trojsi, Francesca; Siciliano, Mattia; Femiano, Cinzia; Santangelo, Gabriella; Lunetta, Christian; Calvo, Andrea; Moglia, Cristina; Marinou, Kalliopi; Ticozzi, Nicola; Drago Ferrante, Gianluca; Scialò, Carlo; Sorarù, Gianni; Conte, Amelia; Falzone, Yuri M; Tortelli, Rosanna; Russo, Massimo; Sansone, Valeria Ada; Chiò, Adriano; Mora, Gabriele; Poletti, Barbara; Volanti, Paolo; Caponnetto, Claudia; Querin, Giorgia; Sabatelli, Mario; Riva, Nilo; Logroscino, Giancarlo; Messina, Sonia; Fasano, Antonio; Monsurrò, Maria Rosaria; Tedeschi, Gioacchino; Mandrioli, Jessica

    2017-11-01

    To assess the association, at diagnosis, between amyotrophic lateral sclerosis (ALS) and dementia in a large cohort of well-characterized Italian patients. We investigated the phenotypic profile of 1638 incident patients with definite, probable or laboratory-supported probable ALS, diagnosed from January 2009 to December 2013 in 13 Italian Referral Centers, located in 10 Italian Regions, and classified in two independent subsamples accounting for presence or not of dementia. The collected ALS features, including survival and other follow-up data, were compared between the two subgroups using a one-way analysis of variance and Chi-square test, as appropriate, logistic regression models and Kaplan-Meier survival analysis. Between-subgroup comparisons showed an older age at clinical observation (p = .006), at onset and at diagnosis (p = .002) in demented versus non demented ALS patients. After adjustment for these variables, diagnosis of dementia was significantly associated with higher odds of family history of ALS (p = .001) and frontotemporal dementia (p = .003) and of bulbar onset (p = .004), and lower odds of flail leg phenotype (p = .019) and spinal onset (p = .008). The median survival time was shorter in demented versus non-demented patients, especially in case of classical, bulbar and flail limb phenotypes and both bulbar and spinal onset. Our multicenter study emphasized the importance of an early diagnosis of comorbid dementia in ALS patients, which may have clinical impact and prognostic relevance. Moreover, our results may give further inputs to validation of ALS-specific tools for the screening of cognitive impairment in clinical practice.

  10. Production of verbs related to body movement in amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD).

    Science.gov (United States)

    Cousins, Katheryn A Q; Ash, Sharon; Grossman, Murray

    2018-03-01

    Theories of grounded cognition propose that action verb knowledge relies in part on motor processing regions, including premotor cortex. Accordingly, impaired action verb knowledge in patients with amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD) is thought to be due to motor system degeneration. Upper motor neuron disease in ALS degrades the motor cortex and related pyramidal motor system, while disease in PD is centered in the basal ganglia and can spread to frontostriatal areas that are important to language functioning. These anatomical distinctions in disease may yield subtle differences in the action verb impairment between patient groups. Here we compare verbs where the body is the agent of the action to verbs where the body is the theme. To examine the role of motor functioning in body verb production, we split patient groups into patients with high motor impairment (HMI) and those with low motor impairment (LMI), using disease-specific measures of motor impairment. Regression analyses assessed how verb production in ALS and PD was related to motor system atrophy. We find a dissociation between agent- and theme-body verbs in ALS: ALS HMI were impaired for agent body verbs but not theme verbs, compared to ALS LMI. This dissociation was not present in PD patients, who instead show depressed production for all body verbs. Although patients with cognitive impairment were excluded from this study, cognitive performance significantly correlated with the production of theme verbs in ALS and cognitive/stative verbs in PD. Finally, regression analyses related the agent-theme dissociation in ALS to grey matter atrophy of premotor cortex. These findings support the view that motor dysfunction and disease in premotor cortex contributes to the agent body verb deficit in ALS, and begin to identify some distinct characteristics of impairment for verbs in ALS and PD. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Profiling Speech and Pausing in Amyotrophic Lateral Sclerosis (ALS and Frontotemporal Dementia (FTD.

    Directory of Open Access Journals (Sweden)

    Yana Yunusova

    Full Text Available This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS and those with frontotemporal dementia (FTD in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls.136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV or progressive nonfluent aphasia (FTD-PNFA. Participants with ALS were further divided into 4 non-overlapping subgroups--mild, respiratory, bulbar (with oral-motor deficit and bulbar-respiratory--based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients.The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures.This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS-FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD.

  12. Soluble RAGE Treatment Delays Progression of Amyotrophic Lateral Sclerosis in SOD1 Mice.

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    Juranek, Judyta K; Daffu, Gurdip K; Geddis, Matthew S; Li, Huilin; Rosario, Rosa; Kaplan, Benjamin J; Kelly, Lauren; Schmidt, Ann Marie

    2016-01-01

    The etiology of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5-10% of cases are familial, and of those, 15-20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs). AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products), and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS vs. wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE), a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention.

  13. A novel automated rodent tracker (ART), demonstrated in a mouse model of amyotrophic lateral sclerosis.

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    Hewitt, Brett M; Yap, Moi Hoon; Hodson-Tole, Emma F; Kennerley, Aneurin J; Sharp, Paul S; Grant, Robyn A

    2018-04-15

    Generating quantitative metrics of rodent locomotion and general behaviours from video footage is important in behavioural neuroscience studies. However, there is not yet a free software system that can process large amounts of video data with minimal user interventions. Here we propose a new, automated rodent tracker (ART) that uses a simple rule-based system to quickly and robustly track rodent nose and body points, with minimal user input. Tracked points can then be used to identify behaviours, approximate body size and provide locomotion metrics, such as speed and distance. ART was demonstrated here on video recordings of a SOD1 mouse model, of amyotrophic lateral sclerosis, aged 30, 60, 90 and 120days. Results showed a robust decline in locomotion speeds, as well as a reduction in object exploration and forward movement, with an increase in the time spent still. Body size approximations (centroid width), showed a significant decrease from P30. ART performed to a very similar accuracy as manual tracking and Ethovision (a commercially available alternative), with average differences in coordinate points of 0.6 and 0.8mm, respectively. However, it required much less user intervention than Ethovision (6 as opposed to 30 mouse clicks) and worked robustly over more videos. ART provides an open-source option for behavioural analysis of rodents, performing to the same standards as commercially available software. It can be considered a validated, and accessible, alternative for researchers for whom non-invasive quantification of natural rodent behaviour is desirable. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients.

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    Mitropoulos, Konstantinos; Merkouri Papadima, Eleni; Xiromerisiou, Georgia; Balasopoulou, Angeliki; Charalampidou, Kyriaki; Galani, Vasiliki; Zafeiri, Krystallia-Vassiliki; Dardiotis, Efthymios; Ralli, Styliani; Deretzi, Georgia; John, Anne; Kydonopoulou, Kyriaki; Papadopoulou, Elpida; di Pardo, Alba; Akcimen, Fulya; Loizedda, Annalisa; Dobričić, Valerija; Novaković, Ivana; Kostić, Vladimir S; Mizzi, Clint; Peters, Brock A; Basak, Nazli; Orrù, Sandro; Kiskinis, Evangelos; Cooper, David N; Gerou, Spyridon; Drmanac, Radoje; Bartsakoulia, Marina; Tsermpini, Evangelia-Eirini; Hadjigeorgiou, Georgios M; Ali, Bassam R; Katsila, Theodora; Patrinos, George P

    2017-12-08

    Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance.

  15. Soluble beta-amyloid precursor protein is related to disease progression in amyotrophic lateral sclerosis.

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    Petra Steinacker

    Full Text Available BACKGROUND: Biomarkers of disease progression in amyotrophic lateral sclerosis (ALS could support the identification of beneficial drugs in clinical trials. We aimed to test whether soluble fragments of beta-amyloid precursor protein (sAPPα and sAPPß correlated with clinical subtypes of ALS and were of prognostic value. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-sectional study including patients with ALS (N = 68 with clinical follow-up data over 6 months, Parkinson's disease (PD, N = 20, and age-matched controls (N = 40, cerebrospinal fluid (CSF levels of sAPPα a, sAPPß and neurofilaments (NfH(SMI35 were measured by multiplex assay, Progranulin by ELISA. CSF sAPPα and sAPPß levels were lower in ALS with a rapidly-progressive disease course (p = 0.03, and p = 0.02 and with longer disease duration (p = 0.01 and p = 0.01, respectively. CSF NfH(SMI35 was elevated in ALS compared to PD and controls, with highest concentrations found in patients with rapid disease progression (p<0.01. High CSF NfH(SMI3 was linked to low CSF sAPPα and sAPPß (p = 0.001, and p = 0.007, respectively. The ratios CSF NfH(SMI35/CSF sAPPα,-ß were elevated in patients with fast progression of disease (p = 0.002 each. CSF Progranulin decreased with ongoing disease (p = 0.04. CONCLUSIONS: This study provides new CSF candidate markers associated with progression of disease in ALS. The data suggest that a deficiency of cellular neuroprotective mechanisms (decrease of sAPP is linked to progressive neuro-axonal damage (increase of NfH(SMI35 and to progression of disease.

  16. Frontal lobe function and behavioral changes in amyotrophic lateral sclerosis: a study from Southwest China.

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    Wei, QianQian; Chen, XuePing; Zheng, ZhenZhen; Huang, Rui; Guo, XiaoYan; Cao, Bei; Zhao, Bi; Shang, Hui-Fang

    2014-12-01

    Despite growing interest, the frequency and characteristics of frontal lobe functional and behavioral deficits in Chinese people with amyotrophic lateral sclerosis (ALS), as well as their impact on the survival of ALS patients, remain unknown. The Chinese version of the frontal assessment battery (FAB) and frontal behavioral inventory (FBI) were used to evaluate 126 sporadic ALS patients and 50 healthy controls. The prevalence of frontal lobe dysfunction was 32.5%. The most notable impairment domain of the FAB was lexical fluency (30.7%). The binary logistic regression model revealed that an onset age older than 45 years (OR 5.976, P = 0.002) and a lower educational level (OR 0.858, P = 0.002) were potential determinants of an abnormal FAB. Based on the FBI score, 46.0% of patients showed varied degrees of frontal behavioral changes. The most common impaired neurobehavioral domains were irritability (25.4%), logopenia (20.6%) and apathy (19.0%). The binary logistic regression model revealed that the ALS Functional Rating Scale-Revised scale score (OR 0.127, P = 0.001) was a potential determinant of an abnormal FBI. Frontal functional impairment and the severity of frontal behavioral changes were not associated with the survival status or the progression of ALS by the cox proportional hazard model and multivariate regression analyses, respectively. Frontal lobe dysfunction and frontal behavioral changes are common in Chinese ALS patients. Frontal lobe dysfunction may be related to the onset age and educational level. The severity of frontal behavioral changes may be associated with the ALSFRS-R. However, the frontal functional impairment and the frontal behavioral changes do not worsen the progression or survival of ALS.

  17. Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial.

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    Weber, M; Goldman, B; Truniger, S

    2010-10-01

    Many patients with amyotrophic lateral sclerosis (ALS) experience cramps during the course of the disease but so far, none of the medications used has been of proven benefit. The objective was to determine the effect of orally administered tetrahydrocannabinol (THC) on cramps in ALS patients. The authors conducted a randomised, double-blind, placebo-controlled crossover trial in 27 ALS patients suffering from moderate to severe (visual analogue scale (VAS); VAS≥4) daily cramps. There were 7 women and 20 men with a mean age of 57 years and a mean functional ALS score (ALSFRS-R) of 38.4. Patients were randomly assigned to receive 5 mg THC twice daily followed by placebo or vice versa. Each treatment period lasted for 2 weeks and was preceded by a 2-week drug-free observation period (run-in, wash-out period respectively). The primary outcome measure was change in cramp intensity as assessed by a VAS. Secondary outcome measures included the number of cramps per day, number of cramps during daytime and bedtime, intensity of fasciculations (VAS) as well as validated measures of quality of life (ALSAQ-40), quality of sleep (SDQ), appetite (FAACT) and depression (HADS). Complete data were available from 22 patients. THC was well tolerated. There was no evidence for a treatment effect on cramp intensity, number of cramps, fasciculation intensity or any of the other secondary outcome measures. This interventional study with orally administered THC 5 mg twice daily did not demonstrate subjective improvement of cramp intensity in ALS patients.

  18. Perception of Emotional Facial Expressions in Amyotrophic Lateral Sclerosis (ALS) at Behavioural and Brain Metabolic Level.

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    Aho-Özhan, Helena E A; Keller, Jürgen; Heimrath, Johanna; Uttner, Ingo; Kassubek, Jan; Birbaumer, Niels; Ludolph, Albert C; Lulé, Dorothée

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) primarily impairs motor abilities but also affects cognition and emotional processing. We hypothesise that subjective ratings of emotional stimuli depicting social interactions and facial expressions is changed in ALS. It was found that recognition of negative emotions and ability to mentalize other's intentions is reduced. Processing of emotions in faces was investigated. A behavioural test of Ekman faces expressing six basic emotions was presented to 30 ALS patients and 29 age-, gender and education matched healthy controls. Additionally, a subgroup of 15 ALS patients that were able to lie supine in the scanner and 14 matched healthy controls viewed the Ekman faces during functional magnetic resonance imaging (fMRI). Affective state and a number of daily social contacts were measured. ALS patients recognized disgust and fear less accurately than healthy controls. In fMRI, reduced brain activity was seen in areas involved in processing of negative emotions replicating our previous results. During processing of sad faces, increased brain activity was seen in areas associated with social emotions in right inferior frontal gyrus and reduced activity in hippocampus bilaterally. No differences in brain activity were seen for any of the other emotional expressions. Inferior frontal gyrus activity for sad faces was associated with increased amount of social contacts of ALS patients. ALS patients showed decreased brain and behavioural responses in processing of disgust and fear and an altered brain response pattern for sadness. The negative consequences of neurodegenerative processes in the course of ALS might be counteracted by positive emotional activity and positive social interactions.

  19. Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis.

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    Yazhou Li

    Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1, facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4 is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells and in vivo (SOD1 G93A mutant mice models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS.

  20. Inflammatory Gene Expression in Whole Peripheral Blood at Early Stages of Sporadic Amyotrophic Lateral Sclerosis

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    Pol Andrés-Benito

    2017-10-01

    Full Text Available ObjectiveCharacterization of altered expression of selected transcripts linked to inflammation in the peripheral blood of sporadic amyotrophic lateral sclerosis (sALS patients at early stage of disease to increase knowledge about peripheral inflammatory response in sALS.MethodsRNA expression levels of 45 genes were assessed by RT-qPCR in 22 sALS cases in parallel with 13 age-matched controls. Clinical and serum parameters were assessed at the same time.ResultsUpregulation of genes coding for factors involved in leukocyte extravasation (ITGB2, INPP5D, SELL, and ICAM1 and extracellular matrix remodeling (MMP9 and TIMP2, as well as downregulation of certain chemokines (CCL5 and CXC5R, anti-inflammatory cytokines (IL10, TGFB2, and IL10RA, pro-inflammatory cytokines (IL-6, and T-cell regulators (CD2 and TRBC1 was found in sALS cases independently of gender, clinical symptoms at onset (spinal, respiratory, or bulbar, progression, peripheral leukocyte number, and integrity of RNA. MMP9 levels positively correlated with age, whereas CCR5, CCL5, and TRBC1 negatively correlated with age in sALS but not in controls. Relatively higher TNFA expression levels correlate with higher creatinine kinase protein levels in plasma.ConclusionPresent findings show early inflammatory responses characterized by upregulation of factors enabling extravasation of leukocytes and extracellular matrix remodeling in blood in sALS cases, in addition to increased TNFA levels paralleling skeletal muscle damage.

  1. The Edinburgh Cognitive and Behavioural ALS Screen in a Chinese Amyotrophic Lateral Sclerosis Population.

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    Shan Ye

    Full Text Available The existing screening batteries assessing multiple neuropsychological functions are not specific to amyotrophic lateral sclerosis (ALS patients and are limited to their physical dysfunctions, whereas category cognitive tests are too time-consuming to assess all the domains. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS was recently developed as a fast and easy cognitive screening tool specifically designed for patients. The purpose of the study was to validate the effectiveness of the Chinese version in Chinese ALS populations.Eighty-four ALS patients and 84 age-, gender- and education-matched healthy controls were included in this cross-sectional study. All the participants took the ECAS, Mini-Mental State Examination (MMSE and Frontal Assessment Battery (FAB. Primary caregivers of patients were interviewed for behavioural and psychiatric changes.Significant differences were noted in language (p = 0.01, fluency, executive function, ALS-specific functions, and ECAS total score (p<0.01 between ALS patients and controls. The cut-off value of the total ECAS score was 81.92. Cognitive impairment was observed in 35.71% of patients, and 27.38% exhibited behavioural abnormalities. The ECAS total score had a medium correlation with education year. Memory was more easily impaired in the lower education group, whereas verbal fluency and language function tended to be preserved in the higher education group. The average time of ECAS was only 18 minutes.The Chinese version of the ECAS is the first screening battery assessing multiple neuropsychological functions specially designed for the ALS population in China, which provides an effective and rapid tool to screen cognitive and behavioural impairments.

  2. Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The Nuedexta Treatment Trial.

    Science.gov (United States)

    Smith, Richard; Pioro, Erik; Myers, Kathleen; Sirdofsky, Michael; Goslin, Kimberly; Meekins, Gregg; Yu, Hong; Wymer, James; Cudkowicz, Merit; Macklin, Eric A; Schoenfeld, David; Pattee, Gary

    2017-07-01

    The goal of this randomized, blinded, crossover clinical trial was to determine whether Nuedexta (dextromethorphan and quinidine) enhanced speech, swallowing, and salivation in patients with ALS. Sixty patients with amyotrophic lateral sclerosis (ALS) received either Nuedexta or placebo for 28 to 30 days, followed by a 10 to 15-day washout period. Subsequently, patients were switched to the opposite treatment arm for the remaining days of the trial. The primary endpoint was a reduction in the self-report Center for Neurologic Study Bulbar Function Scale (CNS-BFS) score. The rater-administered ALS Functional Rating Scale Revised was the principal secondary endpoint. The CNS-BFS score improved with active treatment, decreasing from a mean of 59.3 in the placebo arm of the trial to 53.5 during the drug-treatment arm (p < 0.001). Each of the individual domains of bulbar function interrogated by the CNS-BFS responded to treatment with Nuedexta as follows: salivation: 15.8 versus 14.3 (p = 0.004); speech: 24.6 versus 22.2 (p = 0.003); swallowing: 18.9 versus 17.1 (p = 0.009). Similarly, the bulbar component of the ALS Functional Rating Scale Revised improved with active treatment (p = 0.003), although the drug did not affect the motor and respiratory components of this scale. This study is unique for several reasons. Firstly, it was driven by patient reports of improved speech and swallowing while taking Nuedexta for control of emotional lability. Secondly, the study was conducted over a short duration (70 days), and thirdly, a self-report scale was selected as the principle outcome measure. Considering the importance of bulbar functions, these results, if confirmed, point to an additional use of Nuedexta as an adjunct to the management of ALS.

  3. Percutaneous endoscopic gastrostomy in patients with amyotrophic lateral sclerosis: Mortality and complications.

    Science.gov (United States)

    Carbó Perseguer, J; Madejón Seiz, A; Romero Portales, M; Martínez Hernández, J; Mora Pardina, J S; García-Samaniego, J

    2018-03-26

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes severe dysphagia and weight loss. Percutaneous endoscopic gastrostomy (PEG) is currently the technique of choice for the enteral nutrition of these patients. To analyse mortality and complications in a series of patients diagnosed with ALS who underwent PEG, and to evaluate factors related to patient survival after the procedure. We performed a prospective, observational study including all patients diagnosed with ALS and treated by our hospital's Gastroenterology Department in the period 1997-2013. We studied mortality, complications, and clinical and biochemical parameters, and correlated these with the survival rate. The study included a total of 57 patients, of whom 49 were ultimately treated with PEG. ALS onset was bulbar in 30 patients and spinal in 19. Mortality during the procedure and at 30 days was 2% (n = 1). Six patients (12.2%) experienced major complications; 17 (34.7%) experienced less serious complications which were easily resolved with conservative treatment. No significant differences were observed in forced vital capacity, albumin level, or age between patients with (n = 6) and without (n = 43) major complications. PEG is an effective, relatively safe procedure for the enteral nutrition of patients with ALS, although not without morbidity and mortality. Neither forced vital capacity nor the form of presentation of ALS were associated with morbidity in PEG. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Effectiveness of assisted and unassisted cough capacity in amyotrophic lateral sclerosis patients.

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    Sancho, Jesús; Servera, Emilio; Bañuls, Pilar; Marín, Julio

    2017-11-01

    Decreased cough capacity during a respiratory infection is one of the main causes of acute respiratory failure and hospitalisation in amyotrophic lateral sclerosis (ALS). To determine whether a respiratory measurement could identify the effectiveness of cough capacity in ALS during a respiratory infection. This was a prospective study of all ALS patients who were treated at a respiratory care unit due to a respiratory infection from 2012 to 2016. The effectiveness of unassisted and assisted coughing was evaluated and respiratory function tests were performed during the acute episode. Forty-eight ALS patients were enrolled, with only four having an effective unassisted cough. The variable which predicted unassisted cough effectiveness was peak cough flow (PCF) (OR 4499.27; 95%CI 3.60-3219086.19; p = 0.022) with a cut-off point of 2.77 L/s (166 L/min). For manually assisted coughing, the predictor of cough effectiveness was manually assisted PCF (cut-off point of 2.82-169 L/min) (OR 2198.602; 95% CI 3.750-1351691.42; p = 0.019). Mechanically assisted PCF (cut-off point of 2.95-177 L/min) was found to be the predictor of mechanically assisted coughing effectiveness (OR 23.40; 95% CI 2.11-258.96; p = 0.010). During a respiratory infection in ALS patients, the effectiveness of assisted and unassisted cough capacity depends on the PCF generated.

  5. Whole-brain analysis of amyotrophic lateral sclerosis by using echo-planar spectroscopic imaging.

    Science.gov (United States)

    Verma, Gaurav; Woo, John H; Chawla, Sanjeev; Wang, Sumei; Sheriff, Sulaiman; Elman, Lauren B; McCluskey, Leo F; Grossman, Murray; Melhem, Elias R; Maudsley, Andrew A; Poptani, Harish

    2013-06-01

    To detect regional metabolic differences in amyotrophic lateral sclerosis (ALS) with whole-brain echo-planar spectroscopic imaging. Sixteen patients with ALS (nine men, seven women; mean age, 56.6 years), five persons suspected of having ALS (four men, one woman; mean age, 62.6 years), and 10 healthy control subjects (five men, five women; mean age, 56.1 years) underwent echo-planar spectroscopic imaging after providing informed consent. The study was approved by the institutional review board and complied with HIPAA. Data were analyzed with the Metabolic Imaging and Data Analysis System software, and processed metabolite maps were coregistered and normalized to a standard brain template. Metabolite maps of creatine (Cr), choline (Cho), and N-acetylaspartate (NAA) were segmented into 81 regions with Automated Anatomical Labeling software to measure metabolic changes throughout the brains of patients with ALS. Statistical analysis involved an unpaired, uncorrected, two-sided Student t test. The NAA/Cho ratio across six regions was significantly lower by a mean of 23% (P ≤ .01) in patients with ALS than in control subjects. These regions included the caudate, lingual gyrus, supramarginal gyrus, and right and left superior and right inferior occipital lobes. The NAA/Cr ratio was significantly lower (P ≤ .01) in eight regions in the patient group, by a mean of 16%. These included the caudate, cuneus, frontal inferior operculum, Heschl gyrus, precentral gyrus, rolandic operculum, and superior and inferior occipital lobes. The Cho/Cr ratio did not significantly differ in any region between patient and control groups. Whole-brain echo-planar spectroscopic imaging permits detection of regional metabolic abnormalities in ALS, including not only the motor cortex but also several other regions implicated in ALS pathophysiologic findings.

  6. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis.

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    Van Deerlin, Vivianna M; Leverenz, James B; Bekris, Lynn M; Bird, Thomas D; Yuan, Wuxing; Elman, Lauren B; Clay, Dana; Wood, Elisabeth McCarty; Chen-Plotkin, Alice S; Martinez-Lage, Maria; Steinbart, Ellen; McCluskey, Leo; Grossman, Murray; Neumann, Manuela; Wu, I-Lin; Yang, Wei-Shiung; Kalb, Robert; Galasko, Douglas R; Montine, Thomas J; Trojanowski, John Q; Lee, Virginia M-Y; Schellenberg, Gerard D; Yu, Chang-En

    2008-05-01

    TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1). TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families. We identified two variants in TARDBP, which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available. The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein-protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U. National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació 'la Caixa'.

  7. Grey and white matter changes across the amyotrophic lateral sclerosis-frontotemporal dementia continuum.

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    Patricia Lillo

    Full Text Available There is increasing evidence that amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD lie on a clinical, pathological and genetic continuum with patients of one disease exhibiting features of the other. Nevertheless, to date, the underlying grey matter and white matter changes across the ALS-FTD disease continuum have not been explored. In this study fifty-three participants with ALS (n = 10, ALS-FTD (n = 10 and behavioural variant FTD (bvFTD; n = 15 as well as controls (n = 18, underwent detailed clinical assessment plus structural imaging using voxel-based morphometry (VBM and diffusion tensor imaging (DTI analysis of magnetic resonance brain imaging to examine grey and white matter differences and commonalities across the continuum. Importantly, patient groups were matched for age, education, gender and disease duration. VBM and DTI results showed that changes in the ALS group were confined mainly to the motor cortex and anterior cingulate as well as their underlying white matter tracts. ALS-FTD and bvFTD showed widespread grey matter and white matter changes involving frontal and temporal lobes. Extensive prefrontal cortex changes emerged as a marker for bvFTD compared to other subtypes, while ALS-FTD could be distinguished from ALS by additional temporal lobe grey and white matter changes. Finally, ALS could be mainly distinguished from the other two groups by corticospinal tract degeneration. The present study shows for the first time that FTD and ALS overlap in anterior cingulate, motor cortex and related white matter tract changes across the whole continuum. Nevertheless, frontal and temporal atrophy as well as corticospinal tract degeneration emerged as marker for subtype classification, which will inform future diagnosis and target disease management across the continuum.

  8. Apathy and its impact on patient outcome in amyotrophic lateral sclerosis.

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    Caga, J; Hsieh, S; Highton-Williamson, E; Zoing, M C; Ramsey, E; Devenney, E; Ahmed, R M; Kiernan, M C

    2018-01-01

    Apathy is one of the most common behavioural symptoms of amyotrophic lateral sclerosis (ALS), yet there are few studies that have investigated the relationship between apathy and quality of life (QOL) as they are experienced by the patient. A cohort of 60 ALS patients were evaluated using the Apathy Evaluation Scale which measured cognitive, behavioural, emotional and non-specific symptoms of apathy combined with the Personal Wellbeing Index, a multidimensional measure of QOL. The relationship between patient-rated apathy and QOL scores, controlling for potential clinical and psychological confounders were analysed using univariate and multivariate methods. Apathy was identified in 30% of ALS patients. Patients with apathy reported higher levels of depression (p = 0.0001). Compared to non-apathetic patients, patients with apathy had lower overall QOL (p = 0.001), most pronounced in the domains related to achievements in life (p = 0.001) and community-connectedness (p = 0.0001). Of the cognitive, behavioural, emotional and non-specific manifestations of apathy, only the emotional symptoms explained a significant amount of variance in achievements in life (p = 0.003) and community-connectedness (p = 0.001). As such, emotional manifestations of apathy may underlie worse QOL in ALS patients presenting with behavioural impairment. Patient-reported outcomes, particularly those assessing psychosocial functioning may be important for demonstrating the efficacy of interventions designed to improve QOL in ALS patients with behavioural impairment.

  9. Differences in F-wave characteristics between Spinobulbar Muscular Atrophy and Amyotrophic Lateral Sclerosis

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    Jia eFang

    2016-03-01

    Full Text Available There is limited data on the differences in F-wave characteristics between spinobulbar muscular atrophy (SBMA and lower motor neuron dominant (LMND amyotrophic lateral sclerosis (ALS. We compared the parameters of F-waves recorded bilaterally from the median, ulnar, tibial, and deep peroneal nerves in 32 SBMA patients, 37 patients with LMND ALS, and 30 normal controls. The maximum F-wave amplitudes, frequencies of giant F-waves, and frequencies of patients with giant F-waves in all nerves examined were significantly higher in the SBMA patients than in the ALS patients and the normal controls. The mean F-wave amplitude, maximum F-wave amplitude, frequency of giant F-waves, and frequency of patients with giant F-waves in the median and deep peroneal nerves were comparable between the ALS patients and normal controls. Giant F-waves were detected in multiple nerves and were often symmetrical in the SBMA patients compared with the ALS patients. The number of nerves with giant F-waves seems to be the most robust variable for differentiation of SBMA from ALS, with an area under the curve of 0.908 (95% CI: 0.835–0.982. A cut-off value of the number of nerves with giant F-waves (≥ 3 for diagnosing SBMA showed high sensitivity and specificity: 85% sensitivity and 81% specificity vs. ALS patients. No significant correlations were found between the pooled frequency of giant F-waves and disease duration in the SBMA (r = 0.162, P = 0.418 or ALS groups (r = 0.107, P = 0.529. Our findings suggested that F-waves might be used to discriminate SBMA from ALS, even at early stages of disease.

  10. One Universal Common Endpoint in Mouse Models of Amyotrophic Lateral Sclerosis

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    Solomon, Jesse A.; Tarnopolsky, Mark A.; Hamadeh, Mazen J.

    2011-01-01

    There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS). Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs), CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex), and CS 5 (CS 4 plus righting reflex >20 s). The age (d; mean ± SD) at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001). There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001), CS 4 and CS 4+ (r = 0.96, P<0.001), and CS 4+ and CS 5 (r = 0.98, P<0.001), with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046) and CS 5 (P = 0.006), respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001) from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS? PMID:21687686

  11. What are the roles of carers in decision-making for amyotrophic lateral sclerosis multidisciplinary care?

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    Hogden, Anne; Greenfield, David; Nugus, Peter; Kiernan, Matthew C

    2013-01-01

    Family carers of patients with amyotrophic lateral sclerosis (ALS) are presumed to have frequent involvement in decision-making for symptom management and quality of life. To better understand and improve decision-making, we investigated the range and extent of carer participation in decision-making. By focusing on the perspectives of ALS support carers, the study aimed to explore carer participation in decision-making, to identify carer roles, and determine the facilitators and barriers to carer participation in decision-making for ALS multidisciplinary care. An exploratory, in-depth study was conducted with eight carers of ALS patients from two specialized ALS multidisciplinary clinics. Carers participated in semi-structured interviews that were audio recorded and transcribed then coded and analyzed for emergent themes. Carers made a significant contribution to ALS decision-making. Their roles were: promoting the patient voice, promoting patient health literacy, and providing emotional support and logistical assistance. Facilitators of carer participation in decision-making were perceived to be: health professional endorsement of patients' decision-making style; access to credible information sources; evidence-based information from the ALS clinic, ALS support association, and health practitioners; supportive relationships with family and friends; spiritual faith; ease of contact with ALS services; and availability of physical and practical support for carers. Barriers to carer participation included: changes to patient communication and cognition; conflict between respect for patients' independence and patients' best interest; communication breakdown between patient, carer, and service providers; the confronting nature of disease information; credibility of Internet sites; carer coping strategies; lack of support for the carer; and the burden of care. Carers enhance ALS patient-centered care through their participation in decision-making. They collaborate with

  12. Profiling Speech and Pausing in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

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    Yunusova, Yana; Graham, Naida L.; Shellikeri, Sanjana; Phuong, Kent; Kulkarni, Madhura; Rochon, Elizabeth; Tang-Wai, David F.; Chow, Tiffany W.; Black, Sandra E.; Zinman, Lorne H.; Green, Jordan R.

    2016-01-01

    Objective This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS) and those with frontotemporal dementia (FTD) in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls. Design 136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV) or progressive nonfluent aphasia (FTD-PNFA). Participants with ALS were further divided into 4 non-overlapping subgroups—mild, respiratory, bulbar (with oral-motor deficit) and bulbar-respiratory—based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients. Results The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate) was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures. Conclusions and Relevance This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS—FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD. PMID:26789001

  13. Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis

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    Giniatullina Raisa

    2011-06-01

    Full Text Available Abstract Background Granulocyte colony stimulating factor (GCSF is protective in animal models of various neurodegenerative diseases. We investigated whether pegfilgrastim, GCSF with sustained action, is protective in a mouse model of amyotrophic lateral sclerosis (ALS. ALS is a fatal neurodegenerative disease with manifestations of upper and lower motoneuron death and muscle atrophy accompanied by inflammation in the CNS and periphery. Methods Human mutant G93A superoxide dismutase (SOD1 ALS mice were treated with pegfilgrastim starting at the presymptomatic stage and continued until the end stage. After long-term pegfilgrastim treatment, the inflammation status was defined in the spinal cord and peripheral tissues including hematopoietic organs and muscle. The effect of GCSF on spinal cord neuron survival and microglia, bone marrow and spleen monocyte activation was assessed in vitro. Results Long-term pegfilgrastim treatment prolonged mutant SOD1 mice survival and attenuated both astro- and microgliosis in the spinal cord. Pegfilgrastim in SOD1 mice modulated the inflammatory cell populations in the bone marrow and spleen and reduced the production of pro-inflammatory cytokine in monocytes and microglia. The mobilization of hematopoietic stem cells into the circulation was restored back to basal level after long-term pegfilgrastim treatment in SOD1 mice while the storage of Ly6C expressing monocytes in the bone marrow and spleen remained elevated. After pegfilgrastim treatment, an increased proportion of these cells in the degenerative muscle was detected at the end stage of ALS. Conclusions GCSF attenuated inflammation in the CNS and the periphery in a mouse model of ALS and thereby delayed the progression of the disease. This mechanism of action targeting inflammation provides a new perspective of the usage of GCSF in the treatment of ALS.

  14. Deep learning predictions of survival based on MRI in amyotrophic lateral sclerosis.

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    van der Burgh, Hannelore K; Schmidt, Ruben; Westeneng, Henk-Jan; de Reus, Marcel A; van den Berg, Leonard H; van den Heuvel, Martijn P

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease, with large variation in survival between patients. Currently, it remains rather difficult to predict survival based on clinical parameters alone. Here, we set out to use clinical characteristics in combination with MRI data to predict survival of ALS patients using deep learning, a machine learning technique highly effective in a broad range of big-data analyses. A group of 135 ALS patients was included from whom high-resolution diffusion-weighted and T1-weighted images were acquired at the first visit to the outpatient clinic. Next, each of the patients was monitored carefully and survival time to death was recorded. Patients were labeled as short, medium or long survivors, based on their recorded time to death as measured from the time of disease onset. In the deep learning procedure, the total group of 135 patients was split into a training set for deep learning (n = 83 patients), a validation set (n = 20) and an independent evaluation set (n = 32) to evaluate the performance of the obtained deep learning networks. Deep learning based on clinical characteristics predicted survival category correctly in 68.8% of the cases. Deep learning based on MRI predicted 62.5% correctly using structural connectivity and 62.5% using brain morphology data. Notably, when we combined the three sources of information, deep learning prediction accuracy increased to 84.4%. Taken together, our findings show the added value of MRI with respect to predicting survival in ALS, demonstrating the advantage of deep learning in disease prognostication.

  15. Speech deterioration in amyotrophic lateral sclerosis (ALS) after manifestation of bulbar symptoms.

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    Makkonen, Tanja; Ruottinen, Hanna; Puhto, Riitta; Helminen, Mika; Palmio, Johanna

    2018-03-01

    The symptoms and their progression in amyotrophic lateral sclerosis (ALS) are typically studied after the diagnosis has been confirmed. However, many people with ALS already have severe dysarthria and loss of adequate speech at the time of diagnosis. Speech-and-language therapy interventions should be targeted timely based on communicative need in ALS. To investigate how long natural speech will remain functional and to identify the changes in the speech of persons with ALS. Altogether 30 consecutive participants were studied and divided into two groups based on the initial type of ALS, bulbar or spinal. Their speech disorder was evaluated on severity, articulation rate and intelligibility during the 2-year follow-up. The ability to speak deteriorated to poor and necessitated augmentative and alternative communication (AAC) methods with 60% of the participants. Their speech remained adequate on average for 18 months from the first bulbar symptom. Severity, articulation rate and intelligibility declined with nearly all participants during the study. To begin with speech deteriorated more in the bulbar group than in the spinal group and the difference remained during the whole follow-up with some exceptions. The onset of bulbar symptoms indicated the time to loss of speech better than when assessed from ALS diagnosis or the first speech therapy evaluation. In clinical work, it is important to take the initial type of ALS into consideration when determining the urgency of AAC measures as people with bulbar-onset ALS are more susceptible to delayed evaluation and AAC intervention. © 2017 Royal College of Speech and Language Therapists.

  16. Spreading of amyotrophic lateral sclerosis lesions--multifocal hits and local propagation?

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    Sekiguchi, Teruhiko; Kanouchi, Tadashi; Shibuya, Kazumoto; Noto, Yu-ichi; Yagi, Yohsuke; Inaba, Akira; Abe, Keisuke; Misawa, Sonoko; Orimo, Satoshi; Kobayashi, Takayoshi; Kamata, Tomoyuki; Nakagawa, Masanori; Kuwabara, Satoshi; Mizusawa, Hidehiro; Yokota, Takanori

    2014-01-01

    To investigate whether or not the lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation in the rostrocaudal direction along the spinal cord, as has been hypothesised (the 'single seed and simple propagation' hypothesis). Subjects included 36 patients with sporadic ALS and initial symptoms in the bulbar, respiratory or upper limb regions. Abnormal spontaneous activities in needle electromyography (nEMG)-that is, fibrillation potentials, positive sharp waves (Fib/PSWs) or fasciculation potentials (FPs)-were compared among the unilateral muscles innervated by different spinal segments, especially between the T10 and L5 paraspinal muscles, and between the vastus medialis and biceps femoris. Axon length and the proportion of muscle fibre types, which are both related to motoneuronal vulnerability in ALS, are similar in the paired muscles. Fourteen of 36 patients showed a non-contiguous distribution of nEMG abnormalities from the onset site, with skipping of intermediate segments. In eight of them, the non-contiguous pattern was evident between paired muscles with the same motoneuronal vulnerability. The non-contiguously affected lumbosacral lesions involved motoneuron columns horizontally or radially proximate to one another, appearing to form a cluster in four of the eight patients. FPs, known to precede Fib/PSWs, were shown more frequently than Fib/PSWs in all the lumbosacral segments but L5, suggesting that 2nd hits occur at L5 and then spread to other lumbosacral segments. In sporadic ALS, the distribution of lower motoneuron involvement cannot be explained by the 'single seed and simple propagation' hypothesis alone. We propose a 'multifocal hits and local propagation' hypothesis instead.

  17. Is there a glucose metabolic signature of spreading TDP-43 pathology in Amyotrophic Lateral Sclerosis?

    Science.gov (United States)

    van Weehaeghe, Donatienne; Ceccarini, Jenny; Willekens, Stefanie M; de Vocht, Joke; van Damme, Philip; van Laere, Koen

    2017-11-22

    Recently, four neuropathological stages of amyotrophic lateral sclerosis (ALS) with spreading of transactive response DNA-Binding Protein-43 pathology were described. Although 18F-FDG PET has been useful in diagnosis and prognosis of ALS patients, in vivo disease staging using glucose metabolic patterns across the different ALS stages have not been attempted so far. In this study, we investigated whether the discriminant brain regions of the neuropathological stage model can be translated to metabolic patterns for in vivo staging of ALS. Furthermore, we examined the correlation of these metabolic patterns with disease duration, the Revised ALS Functional Rating Scale (ALSFRS-R) and the Forced Vital Capacity (FVC). 146 ALS patients (age 66.0 ± 11.0 y; 86M/60F) were divided into four metabolic stages depending on glucose metabolism in discriminant regions of neuropathological stages. 18F-FDG data were analysed voxel-based to compare local metabolic patterns between different stages. Additionally, correlation analyses were performed between pathologic stage and clinical parameters. Relative hypometabolism was present in regions known to be affected from the post- mortem pathological spread model, but relative hypermetabolism was also observed across the different ALS stages. In particular, stage 4 reflected a different frontotemporal pattern discordant with mere progression of stage 1-3, which may point to a potential different subgroup in ALS. Furthermore, metabolic stage correlated with disease duration (Spearman ρ = -0.21, p = 0.01) and FVC (Spearman ρ = -0.24, p = 0.04). The neuropathological ALS stages correspond to discriminative regional brain glucose metabolism patterns correlating with disease duration and forced vital capacity. Furthermore, metabolic stage 4 may represents a separate group of ALS progression towards frontotemporal dementia.

  18. Executive dysfunction affects word list recall performance: Evidence from amyotrophic lateral sclerosis and other neurodegenerative diseases.

    Science.gov (United States)

    Consonni, Monica; Rossi, Stefania; Cerami, Chiara; Marcone, Alessandra; Iannaccone, Sandro; Francesco Cappa, Stefano; Perani, Daniela

    2017-03-01

    The Rey Auditory Verbal Learning Test (RAVLT) is widely used in clinical practice to evaluate verbal episodic memory. While there is evidence that RAVLT performance can be influenced by executive dysfunction, the way executive disorders affect the serial position curve (SPC) has not been yet explored. To this aim, we analysed immediate and delayed recall performances of 13 non-demented amyotrophic lateral sclerosis (ALS) patients with a specific mild executive dysfunction (ALSci) and compared their performances to those of 48 healthy controls (HC) and 13 cognitively normal patients with ALS. Moreover, to control for the impact of a severe dysexecutive syndrome and a genuine episodic memory deficit on the SPC, we enrolled 15 patients with a diagnosis of behavioural variant of frontotemporal dementia (bvFTD) and 18 patients with probable Alzheimer's disease (AD). Results documented that, compared to cognitively normal subjects, ALSci patients had a selective mid-list impairment for immediate recall scores. The bvFTD group obtained low performances with a selectively increased forgetting rate for terminal items, whereas the AD group showed a disproportionately large memory loss on the primary and middle part of the SPC for immediate recall scores and were severely impaired in the delayed recall trial. These results suggested that subtle executive dysfunctions might influence the recall of mid-list items, possibly reflecting deficiency in control strategies at retrieval of word lists, whereas severer dysexecutive syndrome might also affect the recall of terminal items possibly due to attention deficit or retroactive interference. © 2015 The British Psychological Society.

  19. Meditation training for people with amyotrophic lateral sclerosis: a randomized clinical trial.

    Science.gov (United States)

    Pagnini, F; Marconi, A; Tagliaferri, A; Manzoni, G M; Gatto, R; Fabiani, V; Gragnano, G; Rossi, G; Volpato, E; Banfi, P; Palmieri, A; Graziano, F; Castelnuovo, G; Corbo, M; Molinari, E; Riva, N; Sansone, V; Lunetta, C

    2017-04-01

    Studies investigating psychological interventions for the promotion of well-being in people with amyotrophic lateral sclerosis (ALS) are lacking. The purpose of the current study was to examine the use of an ALS-specific mindfulness-based intervention for improving quality of life in this population. A randomized, open-label and controlled clinical trial was conducted on the efficacy of an ALS-specific meditation programme in promoting quality of life. Adults who received a diagnosis of ALS within 18 months were randomly assigned either to usual care or to an 8-week meditation training based on the original mindfulness-based stress reduction programme and tailored for people with ALS. Quality of life, assessed with the ALS-Specific Quality of Life Revised scale, represented the primary outcome, whilst secondary outcomes included anxiety and depression, assessed with the Hospital Anxiety and Depression Scale, and specific quality of life domains. Participants were assessed at recruitment and after 2, 6 and 12 months. The efficacy of the treatment was assessed on an intention-to-treat basis of a linear mixed model. A hundred participants were recruited between November 2012 and December 2014. Over time, there was a significant difference between the two groups in terms of quality of life (β = 0.24, P = 0.015, d = 0.89). Significant differences between groups over time were also found for anxiety, depression, negative emotions, and interaction with people and the environment. An ALS-specific meditation programme is beneficial for the quality of life and psychological well-being of people with ALS. © 2017 EAN.

  20. A Case for Microtubule Vulnerability in Amyotrophic Lateral Sclerosis: Altered Dynamics During Disease

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    Jayden A Clark

    2016-09-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is an aggressive multifactorial disease converging on a common pathology: the degeneration of motor neurons, their axons and neuromuscular synapses. This vulnerability and dysfunction of motor neurons highlights the dependency of these large cells on their intracellular machinery. Neuronal microtubules are an intracellular structure that facilitates a myriad of vital neuronal functions, including activity dependent axonal transport. In ALS it is becoming increasingly apparent that microtubules are likely to be a critical component of this disease. Not only are disruptions in this intracellular machinery present in the vast majority of seemingly sporadic cases, recent research has revealed that mutation to a microtubule protein, the tubulin isoform TUBA4A, is sufficient to cause a familial, albeit rare, form of disease. In both sporadic and familial disease, studies have provided evidence that microtubule mediated deficits in axonal transport are the tipping point for motor neuron survivability. Axonal transport deficits would lead to abnormal mitochondrial recycling, decreased vesicle and mRNA transport and limited signalling of key survival factors from the neurons peripheral synapses, causing the characteristic peripheral ‘die back’. This disruption to microtubule dependant transport in ALS has been shown to result from alterations in the phenomenon of microtubule dynamic instability: the rapid growth and shrinkage of microtubule polymers. This is accomplished primarily due to aberrant alterations to microtubule associated proteins (MAPS that regulate microtubule stability. Indeed, the current literature would argue that microtubule stability, particularly alterations in their dynamics, may be the initial driving force behind many familial and sporadic insults in ALS. Pharmacological stabilisation of the microtubule network offers an attractive therapeutic strategy in ALS; indeed it has shown promise in

  1. Angiogenin induces modifications in the astrocyte secretome: relevance to amyotrophic lateral sclerosis.

    Science.gov (United States)

    Skorupa, Alexandra; Urbach, Serge; Vigy, Oana; King, Matthew A; Chaumont-Dubel, Séverine; Prehn, Jochen H M; Marin, Philippe

    2013-10-08

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting lower and upper motoneurons. Recent studies have shown that both motor neurons and non-neuronal neighbouring cells such as astrocytes and microglia contribute to disease pathology. Loss-of-function mutations in the angiogenin (ANG) gene have been identified in ALS patients. Angiogenin is enriched in motor neurons and exerts neuroprotective effects in vitro and in vivo. We have recently shown that motoneurons secrete angiogenin, and that secreted angiogenin is exclusively taken up by astrocytes, suggesting a paracrine mechanism of neuroprotection. To gain insights into astrocyte effectors of angiogenin-induced neuroprotection, we examined alterations in the astrocyte secretome induced by angiogenin treatment using quantitative proteomics based on Stable Isotope Labelling by Amino Acids in Cell Culture (SILAC). We identified 2128 proteins in conditioned media from primary cultured mouse astrocytes, including 1247 putative secreted proteins. Of these, 60 proteins showed significant regulation of secretion in response to angiogenin stimulation. Regulated proteins include chemokines and cytokines, proteases and protease inhibitors as well as proteins involved in reorganising the extracellular matrix. In conclusion, this proteomic analysis increases our knowledge of the astrocyte secretome and reveals potential molecular substrates underlying the paracrine, neuroprotective effects of angiogenin. This study provides the most extensive list of astrocyte-secreted proteins available and reveals novel potential molecular substrates of astrocyte-neuron communication. It also identifies a set of astrocyte-derived proteins that might slow down ALS disease progression. It should be relevant to a large readership of neuroscientists and clinicians, in particular those with an interest in the physiological and pathological roles of astrocytes and in the molecular and cellular mechanisms underlying

  2. Survival prediction in Amyotrophic lateral sclerosis based on MRI measures and clinical characteristics.

    Science.gov (United States)

    Schuster, Christina; Hardiman, Orla; Bede, Peter

    2017-04-17

    Amyotrophic lateral sclerosis (ALS) a highly heterogeneous neurodegenerative condition. Accurate diagnostic, monitoring and prognostic biomarkers are urgently needed both for individualised patient care and clinical trials. A multimodal magnetic resonance imaging study is presented, where MRI measures of ALS-associated brain regions are utilised to predict 18-month survival. A total of 60 ALS patients and 69 healthy controls were included in this study. 20% of the patient sample was utilised as an independent validation sample. Surface-based morphometry and diffusion tensor white matter parameters were used to identify anatomical patterns of neurodegeneration in 80% of the patient sample compared to healthy controls. Binary logistic ridge regressions were carried out to predict 18-month survival based on clinical measures alone, MRI features, and a combination of clinical and MRI data. Clinical indices included age at symptoms onset, site of disease onset, diagnostic delay from first symptom to diagnosis, and physical disability (ALSFRS-r). MRI features included the average cortical thickness of the precentral and paracentral gyri, the average fractional anisotropy, radial-, medial-, and axial diffusivity of the superior and inferior corona radiata, internal capsule, cerebral peduncles and the genu, body and splenium of the corpus callosum. Clinical data alone had a survival prediction accuracy of 66.67%, with 62.50% sensitivity and 70.84% specificity. MRI data alone resulted in a prediction accuracy of 77.08%, with 79.16% sensitivity and 75% specificity. The combination of clinical and MRI measures led to a survival prediction accuracy of 79.17%, with 75% sensitivity and 83.34% specificity. Quantitative MRI measures of ALS-specific brain regions enhance survival prediction in ALS and should be incorporated in future clinical trial designs.

  3. Elucidation of Relevant Neuroinflammation Mechanisms Using Gene Expression Profiling in Patients with Amyotrophic Lateral Sclerosis.

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    Yu Hui Won

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive neurodegenerative disorder characterized by damage of motor neurons. Recent reports indicate that inflammatory responses occurring within the central nervous system contribute to the pathogenesis of ALS. We aimed to investigate disease-specific gene expression associated with neuroinflammation by conducting transcriptome analysis on fibroblasts from three patients with sporadic ALS and three normal controls. Several pathways were found to be upregulated in patients with ALS, among which the toll-like receptor (TLR and NOD-like receptor (NLR signaling pathways are related to the immune response. Genes-toll-interacting protein (TOLLIP, mitogen-activated protein kinase 9 (MAPK9, interleukin-1β (IL-1β, interleukin-8 (IL-8, and chemokine (C-X-C motif ligand 1 (CXCL1-related to these two pathways were validated using western blotting. This study validated the genes that are associated with TLR and NLR signaling pathways from different types of patient-derived cells. Not only fibroblasts but also induced pluripotent stem cells (iPSCs and neural rosettes from the same origins showed similar expression patterns. Furthermore, expression of TOLLIP, a regulator of TLR signaling pathway, decreased with cellular aging as judged by changes in its expression through multiple passages. TOLLIP expression was downregulated in ALS cells under conditions of inflammation induced by lipopolysaccharide. Our data suggest that the TLR and NLR signaling pathways are involved in pathological innate immunity and neuroinflammation associated with ALS and that TOLLIP, MAPK9, IL-1β, IL-8, and CXCL1 play a role in ALS-specific immune responses. Moreover, changes of TOLLIP expression might be associated with progression of ALS.

  4. Analysis of the neurofilament heavy subunit (NFH) gene in familial amyotrophic lateral sclerosis

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    Rooke, K.; Rouleau, G.A. [McGill Univ., Montreal (Canada); Figlewicz, D.A. [Univ. of Rochester Medical Center, NY (United States)

    1994-09-01

    Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, degenerative disorder of the motor neurons in the cortex, brainstem and spinal cord. Approximately 10% of ALS cases are familial (FALS) and are inherited as an age-dependent autosomal dominant trait. Mutations in the Cu/Zn superoxide dismutase (SOD-1) gene on chromosome 21 have been found in a subset of cases. However, for the remaining FALS cases, the etiology is unknown. The abnormal accumulation of neurofilaments in the cell body and proximal axon of motor neurons is a characteristic pathological finding in ALS. Furthermore, aberrant neuronal swellings that closely resemble those found in ALS have been reported in transgenic mice overexpressing NFH. The C-terminal region of NFH contains a unique functional domain with multiple repeats of the amino acids (Lys-Ser-Pro) (KSP) and forms the side-arms which appear, at the level of electron microscopy, to cross-link neurofilaments. Recently, deletions in the DSP repeat domain have been identified in five ALS patients diagnosed as sporadic cases of the disease. Based on these findings, we propose to analyze all 4 exons of the NFH gene for variation in FALS. DNA from 110 FALS cases has been amplified by the polymerase chain reaction (PCR) and analyzed by single strand conformation polymorphism (SSCP) analysis. Exon 2, exon 3 and the KSP repeat domain (part of exon 4) appear normal in all our FALS individuals under several different SSCP conditions. The analysis of exon 1 and the remainder of exon 4 has yet to be completed.

  5. Interhemispheric connectivity in amyotrophic lateral sclerosis: A near-infrared spectroscopy and diffusion tensor imaging study.

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    Kopitzki, Klaus; Oldag, Andreas; Sweeney-Reed, Catherine M; Machts, Judith; Veit, Maria; Kaufmann, Jörn; Hinrichs, Hermann; Heinze, Hans-Jochen; Kollewe, Katja; Petri, Susanne; Mohammadi, Bahram; Dengler, Reinhard; Kupsch, Andreas R; Vielhaber, Stefan

    2016-01-01

    Aim of the present study was to investigate potential impairment of non-motor areas in amyotrophic lateral sclerosis (ALS) using near-infrared spectroscopy (NIRS) and diffusion tensor imaging (DTI). In particular, we evaluated whether homotopic resting-state functional connectivity (rs-FC) of non-motor associated cortical areas correlates with clinical parameters and disease-specific degeneration of the corpus callosum (CC) in ALS. Interhemispheric homotopic rs-FC was assessed in 31 patients and 30 healthy controls (HCs) for 8 cortical sites, from prefrontal to occipital cortex, using NIRS. DTI was performed in a subgroup of 21 patients. All patients were evaluated for cognitive dysfunction in the executive, memory, and visuospatial domains. ALS patients displayed an altered spatial pattern of correlation between homotopic rs-FC values when compared to HCs ( p  = 0.000013). In patients without executive dysfunction a strong correlation existed between the rate of motor decline and homotopic rs-FC of the anterior temporal lobes (ATLs) (ρ = - 0.85, p  = 0.0004). Furthermore, antero-temporal homotopic rs-FC correlated with fractional anisotropy in the central corpus callosum (CC), corticospinal tracts (CSTs), and forceps minor as determined by DTI ( p  < 0.05). The present study further supports involvement of non-motor areas in ALS. Our results render homotopic rs-FC as assessed by NIRS a potential clinical marker for disease progression rate in ALS patients without executive dysfunction and a potential anatomical marker for ALS-specific degeneration of the CC and CSTs.

  6. Ethical considerations and palliative care in patients with amyotrophic lateral sclerosis: A review.

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    Danel-Brunaud, V; Touzet, L; Chevalier, L; Moreau, C; Devos, D; Vandoolaeghe, S; Defebvre, L

    2017-05-01

    Amyotrophic lateral sclerosis (ALS) is not a curable disease, but it is treatable. By definition, much of the care provided to ALS patients is palliative, even though active life-sustaining strategies are available to prolong survival. Healthcare professionals must develop communication skills that help patients cope with the inexorable progression of the disease and the inevitability of death. Symptomatic treatments as well as respiratory insufficiency and nutritional life-sustaining therapies must be regularly evaluated as the disease progresses, without losing sight of the burden placed on the patient's non-professional caregivers. The decision-making process regarding tracheostomy with invasive ventilation (TIV) is of greater complexity. Providing full information is crucial. Several long interviews are necessary to explain, discuss and allow assimilation of the information. Also, physicians should be careful not to focus exclusively on the biomedical aspects of disease, as ALS patients generally welcome the opportunity to discuss end-of-life issues with their physicians. Psychological factors, education level and cognitive status (especially the level of executive dysfunction) have a major influence on their decisions. However, as many patients do not complete advance directives with regard to TIV, advance care planning may instead be suggested in anticipation of emergency interventions. This should be discussed by healthcare professionals and the patient, and based on the wishes of the patient and caregiver(s), and communicated to all healthcare professionals. Many healthcare professionals are involved in the management of an ALS patient: they include not only those at ALS centers who provide diagnosis, follow-up and treatment initiation (particularly for respiratory and nutritional care), but also the medical and social care networks involved in disability support and home care. Specialist palliative care teams can work in partnership with ALS centers early

  7. Evaluating the levels of interleukin-1 family cytokines in sporadic amyotrophic lateral sclerosis

    Science.gov (United States)

    2014-01-01

    Background Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 family cytokines (IL-1β, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), Methods Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. Results Among the IL-1 family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. Conclusions Among the IL-1 family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed. PMID:24884937

  8. Leukocyte-derived microparticles and scanning electron microscopic structures in two fractions of fresh cerebrospinal fluid in amyotrophic lateral sclerosis: a case report

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    Zachau Anne C

    2012-09-01

    Full Text Available Abstract Introduction Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by degeneration of motoneuron cells in anterior spinal horns. There is a need for early and accurate diagnosis with this condition. In this case report we used two complementary methods: scanning electron microscopy and fluorescence-activated cell sorting. This is the first report to our knowledge of microparticles in the cerebrospinal fluid of a patient with amyotrophic lateral sclerosis. Case presentation An 80-year-old Swedish man of Caucasian ethnicity presented to our facility with symptoms of amyotrophic lateral sclerosis starting a year before his first hospital examination, such as muscle weakness and twitching in his right hand progressing to arms, body and leg muscles. Electromyography showed classical neurophysiological findings of amyotrophic lateral sclerosis. Routine blood sample results were normal. A lumbar puncture was performed as a routine investigation and his cerebrospinal fluid was normal with regard to cell count and protein levels, and there were no signs of inflammation. However, scanning electron microscopy and fluorescence-activated cell sorting showed pronounced abnormalities compared to healthy controls. Flow cytometry analysis of two fractions of cerebrospinal fluid from our patient with amyotrophic lateral sclerosis was used to measure the specific binding of antibodies to CD42a, CD144 and CD45, and of phosphatidylserine to lactadherin. Our patient displayed over 100 times more phosphatidylserine-positive microparticles and over 400 times more cell-derived microparticles of leukocyte origin in his cerebrospinal fluid compared to healthy control subjects. The first cerebrospinal fluid fraction contained about 50% more microparticles than the second fraction. The scanning electron microscopy filters used with cerebrospinal fluid from our patient were filled with compact aggregates of spherical particles of

  9. Self-management of nocturnal respiratory insufficiency with a portable ventilator "Pneu-PAC" by an amyotrophic lateral sclerosis patient.

    Science.gov (United States)

    Hoshino, K; Kuroda, A; Mizushima, Y; Morikage, T; Yano, S

    1991-01-01

    A 76-year-old man with amyotrophic lateral sclerosis was admitted to our hospital because of progressive exertional dyspnea (PaCO2 = 68.5 torr, PaO2 = 62.5 torr). He was put on mechanical ventilation, and thereafter sleep apnea of a central type was recognized. After improvement of general conditions, a portable ventilator "Pneu-PAC" was used for the self-management of nocturnal respiratory insufficiency. A portable ventilator might be of clinical benefit for the management of a patient with neuromuscular disorder whose activities of daily living are still functional.

  10. Syndrome of Inappropriate Antidiuretic Hormone Secretion Associated with Amyotrophic Lateral Sclerosis in a Patient Developing Carbon Dioxide Narcosis.

    Science.gov (United States)

    Inoue, Yui; Murakami, Takaaki; Nakamura, Takeshi; Morita, Kyohei; Kaneda, Daita; Nishino, Ichizo; Hayashi, Tetsuya; Shinoto, Yuya; Hatoko, Tomonobu; Kato, Tomoko; Yonemitsu, Shin; Muro, Seiji; Oki, Shogo

    2017-01-01

    We report a rare case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with amyotrophic lateral sclerosis (ALS). A 69-year-old man was admitted to our hospital with sustained hyponatremia. Hyposmolality with elevated urinary osmolality and sodium excretion was observed, which indicated SIADH. The treatment for SIADH was challenging; the patient developed carbon dioxide narcosis, which led to the diagnosis of ALS. After the initiation of noninvasive positive-pressure ventilation, the patient's serum sodium concentration normalized and became stable. Thus, ALS should be recognized as a possible cause of SIADH in the clinical setting.

  11. Amyotrophic lateral sclerosis with dementia: case report Esclerose lateral amiotrófica com demência: relato de caso

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    PAULO ROBERTO DE BRITO-MARQUES

    1999-06-01

    Full Text Available A patient is described in whom a profound and rapidly progressive dementia occurred in association with clinical features of amyotrophic lateral sclerosis. A magnetic resonance imaging showed signs of frontal and especially left temporal atrophy. The pattern of dementia indicated impaired frontotemporal lobe functions, evidenced by reduced tracer uptake in the frontotemporal lobes on brain single photon emission computed tomography. Neuropathological examination in this patient revealed mild frontotemporal atrophy with spongiform changes and neuronal loss affecting mainly layers II and III of the frontotemporal cortices. There was atrophy of the hypoglossal nuclei. The spinal cord changes were consistent with motor neuron disease. The patient showed an irreversible and progressive course. A review of the relevant literature was made.Demência de evolução rápida e progressiva associada com esclerose lateral amiotrófica ocorreu em uma paciente de 68 anos. A ressonância magnética mostrou sinais de atrofia frontal e, principalmente, temporal bilateral mais acentuada à esquerda. A demência se caracterizou como de tipo fronto-temporal, como sugere por hipoperfusão moderada nos lobos fronto-temporais através da tomografia cerebral computadorizada por emissão de fóton simples. O exame neuropatológico revelou atrofia leve fronto-temporal com alterações esponjiformes e perda neuronal afetando principalmente as camadas II e III dos córtices fronto-temporais. Havia importante perda de neurônios em ambos os núcleos do hipoglosso. A medula espinhal mostrou alterações consistentes com doença do neurônio motor. O caso teve curso de quatro anos até o óbito.

  12. Esclerose lateral amiotrófica e neurossífilis Amyotrophic lateral sclerosis and neurosyphilis. A case report

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    Eliova Zukerman

    1973-09-01

    Full Text Available É relatado um caso clínico de esclerose lateral amiotrófica (ELA, caracterizado por amiotrofias extensas na cintura escapular e membros superiores, associadas a exaltação dos reflexos osteotendinosos nos membros inferiores, com sinal de Rossolimo bilateral e sinal Babinski esboçado a esquerda, sem distúrbios sensitivos ou esfinterianos, em mulher de 51 anos de idade e com história progressiva de um ano. O exame de líquido cefalorraqueano permitiu o diagnóstico de neurossífilis parenquimatosa. Chamando a atenção para a raridade dessa associação, os AA. discutem o papel da neuro-lues como fator causal da síndrome de ELA, concluindo por uma provável relação de causa e efeito no caso descrito, por ter havido estabilização do quadro sintomatológico após terapêutica penicilínica.A clinic case of amyotrophic lateral sclerosis (ALS in a 51 years old woman is reported. The patient exhibited signs of pyramidal system and anterior motor neuron involvement. The cerebrospinal fluid examinations showed clear cut indications of parenchymatous neurosyphilis. Attention is called to the rarity of the association above mentioned. The role of neurosyphilis as an atiological factor of ALS is discussed. The authors conclude that in the case described there is a close relationship between the two entities.

  13. Unexpected death of a ventilator-dependent amyotrophic lateral sclerosis patient

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    M. di Paolo

    2013-07-01

    Full Text Available Background: Amyotrophic lateral sclerosis (ALS is a fatal, progressive, neurodegenerative disease and most patients affected die of respiratory compromise and/or pneumonia within 2–3 years of diagnosis. As ALS progresses, ventilator assistance is required. In the end stages of the disease, patients suffer from respiratory failure and may become ventilator-dependent. Deaths due to malfunction of mechanical ventilators are reported but there are very few forensic autopsy records. We report the case of a 69-year-old ALS female ventilator-dependent, trachostomised patient who was found dead by her husband, with the ventilator in “stand-by” mode. Method: A forensic autopsy was performed. Samples of internal organs were taken for histological and toxicological examination. The ventilator internal memory was also analysed and tested in order to find possible malfunction. Results: Gross examination did not reveal any sign of trauma but showed brain and lung congestion. Pulmonary histological examination revealed thickening of peribronchial interstitial space, alveolar over-distension, break of inter-alveolar walls and diffuse alveolar haemorrhages. Focal microhemorrhages were also detected in other organs. Analysis of the ventilator internal memory showed that during the night of death, there had been several voltage drops. Specific tests revealed malfunction of the internal battery which was unable to provide the necessary voltage, as a consequence the ventilator switched off, stopping ventilation. Battery malfunction reduced the volume of the ventilator alarm, which was not heard by the caregiver. Conclusion: Histological pattern, with acute pulmonary emphysema and focal polivisceral haemorrhages, is strongly suggestive of a death due to “acute” asphyxia. The authors also discuss the need for strict supervision and follow up of these ventilatory dependent patients and their devices. Resumo: Introdução: A Esclerose

  14. [Causes of death in amyotrophic lateral sclerosis : Results from the Rhineland-Palatinate ALS registry].

    Science.gov (United States)

    Wolf, J; Safer, A; Wöhrle, J C; Palm, F; Nix, W A; Maschke, M; Grau, A J

    2017-08-01

    Amyotrophic lateral sclerosis (ALS) is associated with an increased mortality. Knowledge of possible causes of death could lead to an individualization of the palliative treatment concept and result in a differentiated palliative treatment pathway. Currently, only few systematic data are available on the heterogeneity of causes of death associated with ALS. Analysis of the various causes of death in a prospective population-based German cohort of ALS patients. Analysis of data of the Rhineland-Palatinate ALS registry in which newly diagnosed patients who had been identified between October 2009 and September 2012 were prospectively enrolled and followed up at regular intervals. From this prospective cohort study the causes of death were elicited based on information provided by the attending physicians, family members and by means of death certificates registered by the regional health authorities in Rhineland-Palatinate. Out of 200 ALS patients registered 148 died between register initiation on 1 October 2009 and the end of follow-up on 30 September 2015 (78 males and 70 females, death rate 74%). The most frequent cause of death was respiratory failure as a consequence of weakness of respiratory muscles (n = 91, 61%). Less frequent causes of death were pneumonia (n = 13, 9%), terminal cachexia (n = 9, 6%) and death from cardiovascular causes including sudden death (n = 9, 6%). Cases of suicide were rare (n = 3, 2%) as were deaths due to concurrent diseases (n = 2). In 21 cases (14%) the exact cause of death could not be clarified. Differences in the causes of death only showed a tendency towards the ALS phenotype. Respiratory failure was the cause of death in all patients with a respiratory phenotype and in 78% of patients with flail arm syndrome. Despite the low number of patients (8%) with additional frontotemporal dementia (FTD) a distinct difference in causes of death between those with and without FTD could be observed. Death due to respiratory

  15. Serum C-Reactive Protein as a Prognostic Biomarker in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Lizio, Andrea; Maestri, Eleonora; Sansone, Valeria Ada; Mora, Gabriele; Miller, Robert G.; Appel, Stanley H.; Chiò, Adriano

    2017-01-01

    Importance Various factors have been proposed as possible candidates associated with the prognosis of amyotrophic lateral sclerosis (ALS); however, there is still no consensus on which biomarkers are reliable prognostic factors. C-reactive protein (CRP) is a biomarker of the inflammatory response that shows significant prognostic value for several diseases. Objective To examine the prognostic significance of CRP in ALS. Design, Setting, and Participants Patients’ serum CRP levels were evaluated from January 1, 2009, to June 30, 2015, in a large cohort of patients with ALS observed by an Italian tertiary multidisciplinary center. Results were replicated in an independent cohort obtained from a population-based registry of patients with ALS. A post hoc analysis was performed of the phase 2 trial of NP001 to determine whether stratification by levels of CRP improves differentiation of responders and nonresponders to the drug. Main Outcomes and Measures Serum CRP levels from the first examination were recorded to assess their effect on disease progression and survival. Results A total of 394 patients with ALS (168 women and 226 men; mean [SD] age at diagnosis, 60.18 [13.60] years) were observed in a tertiary multidisciplinary center, and the analysis was replicated in an independent cohort of 116 patients with ALS (50 women and 66 men; mean [SD] age at diagnosis, 67.00 [10.74] years) identified through a regional population-based registry. Serum CRP levels in the 394 patients with ALS correlated with severity of functional impairment, as measured by total score on the ALS Functional Rating Scale–Revised, at first evaluation (r = –0.14818; P = .004), and with patient survival (hazard ratio, 1.129; 95% CI, 1.033-1.234; P = .007). Similar results were found in the independent cohort (hazard ratio, 1.044; 95% CI, 1.016-1.056; P ≤ .001). Moreover, a post hoc analysis of the phase 2 trial of NP001 using the same CRP threshold showed that patients with

  16. Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice.

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    Rebecca Banerjee

    2008-07-01

    Full Text Available Innate neuroimmune dysfunction is a pathobiological feature of amyotrophic lateral sclerosis (ALS. However, links, if any, between disease and adaptive immunity are poorly understood. Thus, the role of T cell immunity in disease was investigated in human G93A superoxide dismutase 1 (SOD1 transgenic (Tg mice and subsequently in ALS patients.Quantitative and qualitative immune deficits in lymphoid cell and T cell function were seen in G93A-SOD1 Tg mice. Spleens of Tg animals showed reductions in size, weight, lymphocyte numbers, and morphological deficits at terminal stages of disease compared to their wild-type (Wt littermates. Spleen sizes and weights of pre-symptomatic Tg mice were unchanged, but deficits were readily seen in T cell proliferation coincident with increased annexin-V associated apoptosis and necrosis of lymphocytes. These lymphoid deficits paralleled failure of Copolymer-1 (COP-1 immunization to affect longevity. In addition, among CD4(+ T cells in ALS patients, levels of CD45RA(+ (naïve T cells were diminished, while CD45RO(+ (memory T cells were increased compared to age-matched caregivers. In attempts to correct mutant SOD1 associated immune deficits, we reconstituted SOD1 Tg mice with unfractionated naïve lymphocytes or anti-CD3 activated CD4(+CD25(+ T regulatory cells (Treg or CD4(+CD25(- T effector cells (Teff from Wt donor mice. While naive lymphocytes failed to enhance survival, both polyclonal-activated Treg and Teff subsets delayed loss of motor function and extended survival; however, only Treg delayed neurological symptom onset, whereas Teff increased latency between disease onset and entry into late stage.A profound and progressive immunodeficiency is operative in G93A-SOD1 mice and is linked to T cell dysfunction and the failure to elicit COP-1 neuroprotective immune responses. In preliminary studies T cell deficits were also observed in human ALS. These findings, taken together, suggest caution in ascribing

  17. CX3CR1 is a modifying gene of survival and progression in amyotrophic lateral sclerosis.

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    Alan Lopez-Lopez

    Full Text Available The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor with the risk of Amyotrophic Lateral Sclerosis (ALS, the survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142 sporadic [sALS] and 45 familial and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379 and T280M (rs3732378 genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.27 ± 4.90 than patients with 249V/V genotype (67.65 ± 7.42; diff -25.49 months 95%CI [-42.79,-8.18]; p = 0.004; adj-p = 0.018. The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff =  -29.78 months; 95%CI [-49.42,-10.14]; p = 0.003. The same effects were also observed in the spinal sALS patients with 249I-280M haplotype (diff =  -27.02 months; 95%CI [-49.57, -4.48]; p = 0.019. In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR = 2.58; 95IC% [1.32, 5.07]; p = 0.006; adj-p = 0.027. There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the disease's symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis.

  18. Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial.

    Science.gov (United States)

    Park, Susanna B; Vucic, Steve; Cheah, Benjamin C; Lin, Cindy S-Y; Kirby, Adrienne; Mann, Kristy P; Zoing, Margie C; Winhammar, Jennica; Kiernan, Matthew C

    2015-12-01

    Abnormalities in membrane excitability and Na(+) channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability of the Na(+) channel blocker and membrane stabiliser flecainide in ALS. A double-blind, placebo-controlled, randomised clinical trial of flecainide (200 mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period. Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 [95% CI 0.49 to 0.98]; Placebo 0.81 [0.49 to 2.12] P = 0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 [0.01 to 0.11]; Placebo 0.14 [0.09 to 0.19], P = 0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: - 15 ± 12%; Placebo - 59 ± 12%; P = 0.03). Flecainide

  19. Bee venom attenuates neuroinflammatory events and extends survival in amyotrophic lateral sclerosis models

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    Lee Myeong Soo

    2010-10-01

    Full Text Available Abstract Background Amyotrophic lateral sclerosis (ALS is a disease affecting the central nervous system that is either sporadic or familial origin and causing the death of motor neurons. One of the genetic factors contributing to the etiology of ALS is mutant SOD1 (mtSOD1, which induces vulnerability of motor neurons through protein misfolding, mitochondrial dysfunction, oxidative damage, cytoskeletal abnormalities, defective axonal transport, glutamate excitotoxicity, inadequate growth factor signaling, and neuroinflammation. Bee venom has been used in the practice of Oriental medicine and evidence from the literature indicates that BV plays an anti-inflammatory or anti-nociceptive role against inflammatory reactions associated with arthritis and other inflammatory diseases. The purpose of the present study was to determine whether bee venom suppresses motor neuron loss and microglial cell activation in hSOD1G93A mutant mice. Methods Bee venom (BV was bilaterally injected (subcutaneously into a 14-week-old (98 day old male hSOD1G93A animal model at the Zusanli (ST36 acupoint, which is known to mediate an anti-inflammatory effect. For measurement of motor activity, rotarod test was performed and survival statistics were analyzed by Kaplan-Meier survival curves. The effects of BV treatment on anti-neuroinflammation of hSOD1G93A mice were assessed via immunoreactions using Iba 1 as a microglia marker and TNF-α antibody. Activation of ERK, Akt, p38 MAP Kinase (MAPK, and caspase 3 proteins was evaluated by western blotting. Results BV-treated mutant hSOD1 transgenic mice showed a decrease in the expression levels of microglia marker and phospho-p38 MAPK in the spinal cord and brainstem. Interestingly, treatment of BV in symptomatic ALS animals improved motor activity and the median survival of the BV-treated group (139 ± 3.5 days was 18% greater than control group (117 ± 3.1 days. Furthermore, we found that BV suppressed caspase-3 activity and

  20. Defining Swallowing-Related Quality of Life Profiles in Individuals with Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Tabor, Lauren; Gaziano, Joy; Watts, Stephanie; Robison, Raele; Plowman, Emily K

    2016-06-01

    Although it is known that dysphagia contributes to significant malnutrition, pneumonia, and mortality in amyotrophic lateral sclerosis (ALS), it remains unclear how swallowing impairment impacts quality of life in this vulnerable patient population. The aim of the current study was to (1) delineate swallow-related quality of life (SR-QOL) profiles in individuals with ALS and (2) evaluate relationships between SR-QOL, degree of swallowing impairment, and ALS global disease progression. Eighty-one ALS patients underwent a standardized videofluoroscopic swallow study and completed the swallowing quality of life (SWAL-QOL) instrument and ALS functional rating scale-revised (ALSFRS-R). Penetration Aspiration Scale (PAS) scores were derived by a blinded rater. Correlation analyses and a between groups ANOVA (safe vs. penetrators vs. aspirators) were performed. Mean SWAL-QOL score for this cohort was 75.94 indicating a moderate degree of SR-QOL impairment with fatigue, eating duration, and communication representing the most affected domains. Correlations were revealed between the SWAL-QOL and (1) PAS (r = -0.39, p < 0.001) and (2) ALSFRS-R (r = 0.23, p < 0.05). Mean (SD) SWAL-QOL scores for safe versus penetrator versus aspirator groups were 81.2 (2.3) versus 77 (3.4) versus 58.7 (5.9), respectively, with a main effect observed [F(2,78) = 9.71, p < 0.001]. Post hoc testing revealed lower SWAL-QOL scores for aspirators versus safe swallowers (p < 0.001) and aspirators versus penetrators (p < 0.001). Overall, SR-QOL was moderately reduced in this cohort of ALS patients and profoundly impacted in ALS aspirators and individuals with advanced disease. These findings highlight the importance of early multidisciplinary intervention to not only avoid malnutrition, weight loss, and pulmonary sequelae but also the associated reduced QOL seen in these individuals.

  1. One universal common endpoint in mouse models of amyotrophic lateral sclerosis.

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    Jesse A Solomon

    Full Text Available There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS. Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs, CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex, and CS 5 (CS 4 plus righting reflex >20 s. The age (d; mean ± SD at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001. There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001, CS 4 and CS 4+ (r = 0.96, P<0.001, and CS 4+ and CS 5 (r = 0.98, P<0.001, with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046 and CS 5 (P = 0.006, respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001 from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS?

  2. New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background.

    Science.gov (United States)

    Penco, Silvana; Buscema, Massimo; Patrosso, Maria Cristina; Marocchi, Alessandro; Grossi, Enzo

    2008-05-30

    Few genetic factors predisposing to the sporadic form of amyotrophic lateral sclerosis (ALS) have been identified, but the pathology itself seems to be a true multifactorial disease in which complex interactions between environmental and genetic susceptibility factors take place. The purpose of this study was to approach genetic data with an innovative statistical method such as artificial neural networks to identify a possible genetic background predisposing to the disease. A DNA multiarray panel was applied to genotype more than 60 polymorphisms within 35 genes selected from pathways of lipid and homocysteine metabolism, regulation of blood pressure, coagulation, inflammation, cellular adhesion and matrix integrity, in 54 sporadic ALS patients and 208 controls. Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis. An unexpected discovery of a strong genetic background in sporadic ALS using a DNA multiarray panel and analytical processing of the data with advanced artificial neural networks was found. The predictive accuracy obtained with Linear Discriminant Analysis and Standard Artificial Neural Networks ranged from 70% to 79% (average 75.31%) and from 69.1 to 86.2% (average 76.6%) respectively. The corresponding value obtained with Advanced Intelligent Systems reached an average of 96.0% (range 94.4 to 97.6%). This latter approach allowed the identification of seven genetic variants essential to differentiate cases from controls: apolipoprotein E arg158cys; hepatic lipase -480 C/T; endothelial

  3. Elimination Rate of Serum Lactate is Correlated with Amyotrophic Lateral Sclerosis Progression

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    Yuan-Jin Zhang

    2016-01-01

    Full Text Available Background: Mitochondrial dysfunction plays an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS. We aimed to demonstrate mitochondrial dysfunction in ALS using a lactate stress test and to examine the relationship between mitochondrial dysfunction with motor deterioration. Methods: We enrolled 116 patients and observed clinical variables, including the survival state. Results: Patients with a rapid slope of revised ALS functional rating scales (ALSFRS-r (>20 U/year exhibited the slowest elimination rate (median −4.67 × 10−3 mmol·L−1·min−1 , coefficient of variation, 590.15%, the shortest duration (0.63 ± 0.28 years and the worst ALSFRS-r (32.59 ± 4.93. Patients with a moderate slope of ALSFRS-r (10-20 U/year showed a moderate elimination rate (median −11.33 × 10−3 mmol·L−1·min−1 , coefficient of variation, 309.89%, duration (1.16 ± 0.45 years, and ALSFRS-r (34.83 ± 6.11. The slower progressing (<10 U/year group patients exhibited a rapid elimination rate (median: −12.00 × 10−3 mmol·L−1·min−1 , coefficient of variation: 143.08%, longer duration (median: 3 years, coefficient of variation: 193.33%, and adequate ALSFRS-r values (39.58 ± 9.44. Advanced-phase ALS patients also showed slower elimination rate (ER, quartiles −17.33, −5.67, 4.00 and worse ALSFRS-r (34.88 ± 9.27, while early-phase patients showed a more rapid ER (quartiles −25.17, −11.33, −3.50 and better ALSFRS-r (39.28 ± 7.59. These differences were statistically significant. Multiple linear regression analysis revealed strong direct associations among ER, ALSFRS-r slope (standard beta = 0.33, P = 0.007, and forced vital capacity (predict % (standard beta = −0.458, P = 0.006, adjusted for ALSFRS-r, course and onset region. However, the data obtained from 3 years of follow-up showed no statistically significant difference in the survival rates between the most rapid and slowest ER groups. Conclusion: There is a

  4. Correlation of Creatine Kinase Levels with Clinical Features and Survival in Amyotrophic Lateral Sclerosis

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    Hongfei Tai

    2017-07-01

    Full Text Available ObjectiveTo evaluate serum creatine kinase (CK levels of amyotrophic lateral sclerosis (ALS patients and to explore the relationship between CK levels and the clinical characteristics and survival prognosis of ALS patients.MethodsWe analyzed the CK levels of 185 ALS patients who underwent long-term follow-up. The relationship between CK levels and clinical features including sex, age, disease duration, site of onset, body mass index (BMI, serum creatinine (Cr, and spontaneous electromyographic activity was analyzed by univariate analysis and multiple linear regression. Kaplan–Meier and Cox proportional hazards models were used to explore whether CK levels were independently correlated with survival prognosis of ALS.ResultsBaseline serum CK was raised in 43% of participants. The median CK level was 160 U/L (range: 20–2,574 U/L, and 99% of patients had a baseline serum CK level less than 1,000 U/L. CK levels were significantly higher in male patients than in female patients [204 (169 versus 117 (111 U/L, p < 0.001] and in patients with limb onset ALS than with bulbar onset ALS (p < 0.001. CK levels were also correlated with serum Cr (p = 0.011 and the spontaneous potential score of electromyography (EMG (p = 0.037 but not correlated with age (p = 0.883, disease duration (p = 0.116, or BMI (p = 0.481. Log CK was independently correlated with survival of ALS patients (HR = 0.457, 95% confidence interval 0.221–0.947, p = 0.035 after adjusting for age, sex, site of onset, serum Cr, and BMI.ConclusionSerum CK levels of ALS patients were correlated with sex, site of onsite, serum Cr, and spontaneous activity in EMG. Serum CK could be an independent prognostic factor for survival of ALS patients.

  5. Altered nucleocytoplasmic proteome and transcriptome distributions in an in vitro model of amyotrophic lateral sclerosis.

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    Jee-Eun Kim

    Full Text Available Aberrant nucleocytoplasmic localization of proteins has been implicated in many neurodegenerative diseases. Evidence suggests that cytoplasmic mislocalization of nuclear proteins such as transactive response DNA-binding protein 43 (TDP-43 and fused in sarcoma (FUS may be associated with neurotoxicity in amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration. This study investigated the changes in nucleocytoplasmic distributions of the proteome and transcriptome in an in vitro model of ALS. After subcellular fractionation of motor neuron-like cell lines expressing wild-type or G93A mutant hSOD1, quantitative mass spectrometry and next-generation RNA sequencing (RNA-seq were performed for the nuclear and cytoplasmic compartments. A subset of the results was validated via immunoblotting. A total of 1,925 proteins were identified in either the nuclear or cytoplasmic fractions, and 32% of these proteins were quantified in both fractions. The nucleocytoplasmic distribution of 37 proteins was significantly changed in mutant cells with nuclear and cytoplasmic shifts in 13 and 24 proteins, respectively (p<0.05. The proteins shifted towards the nucleus were enriched regarding pathways of RNA transport and processing (Dhx9, Fmr1, Srsf3, Srsf6, Tra2b, whereas protein folding (Cct5, Cct7, Cct8, aminoacyl-tRNA biosynthesis (Farsb, Nars, Txnrd1, synaptic vesicle cycle (Cltc, Nsf, Wnt signalling (Cltc, Plcb3, Plec, Psmd3, Ruvbl1 and Hippo signalling (Camk2d, Plcb3, Ruvbl1 pathways were over-represented in the proteins shifted to the cytoplasm. A weak correlation between the changes in protein and mRNA levels was found only in the nucleus, where mRNA was relatively abundant in mutant cells. This study provides a comprehensive dataset of the nucleocytoplasmic distribution of the proteome and transcriptome in an in vitro model of ALS. An integrated analysis of the nucleocytoplasmic distribution of the proteome and transcriptome demonstrated

  6. The processing of actions and action-words in amyotrophic lateral sclerosis patients.

    Science.gov (United States)

    Papeo, Liuba; Cecchetto, Cinzia; Mazzon, Giulia; Granello, Giulia; Cattaruzza, Tatiana; Verriello, Lorenzo; Eleopra, Roberto; Rumiati, Raffaella I

    2015-03-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with prime consequences on the motor function and concomitant cognitive changes, most frequently in the domain of executive functions. Moreover, poorer performance with action-verbs versus object-nouns has been reported in ALS patients, raising the hypothesis that the motor dysfunction deteriorates the semantic representation of actions. Using action-verbs and manipulable-object nouns sharing semantic relationship with the same motor representations, the verb-noun difference was assessed in a group of 21 ALS-patients with severely impaired motor behavior, and compared with a normal sample's performance. ALS-group performed better on nouns than verbs, both in production (action and object naming) and comprehension (word-picture matching). This observation implies that the interpretation of the verb-noun difference in ALS cannot be accounted by the relatedness of verbs to motor representations, but has to consider the role of other semantic and/or morpho-phonological dimensions that distinctively define the two grammatical classes. Moreover, this difference in the ALS-group was not greater than the noun-verb difference in the normal sample. The mental representation of actions also involves an executive-control component to organize, in logical/temporal order, the individual motor events (or sub-goals) that form a purposeful action. We assessed this ability with action sequencing tasks, requiring participants to re-construct a purposeful action from the scrambled presentation of its constitutive motor events, shown in the form of photographs or short sentences. In those tasks, ALS-group's performance was significantly poorer than controls'. Thus, the executive dysfunction manifested in the sequencing deficit -but not the selective verb deficit- appears as a consistent feature of the cognitive profile associated with ALS. We suggest that ALS can offer a valuable model to study the relationship between

  7. A Metadata Analysis of Oxidative Stress Etiology in Preclinical Amyotrophic Lateral Sclerosis: Benefits of Antioxidant Therapy

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    Leila Bond

    2018-01-01

    Full Text Available Oxidative stress, induced by an imbalance of free radicals, incites neurodegeneration in Amyotrophic Lateral Sclerosis (ALS. In fact, a mutation in antioxidant enzyme superoxide dismutase 1 (SOD1 accounts for 20% of familial ALS cases. However, the variance among individual studies examining ALS oxidative stress clouds corresponding conclusions. Therefore, we construct a comprehensive, temporal view of oxidative stress and corresponding antioxidant therapy in preclinical ALS by mining published quantitative experimental data and performing metadata analysis of 41 studies. In vitro aggregate analysis of innate oxidative stress inducers, glutamate and hydrogen peroxide, revealed 70–90% of cell death coincides to inducer exposure equivalent to 30–50% peak concentration (p < 0.05. A correlative plateau in cell death suggests oxidative stress impact is greatest in early-stage neurodegeneration. In vivo SOD1-G93A transgenic ALS mouse aggregate analysis of heat shock proteins (HSPs revealed HSP levels are 30% lower in muscle than spine (p < 0.1. Overall spine HSP levels, including HSP70, are mildly upregulated in SOD1-G93A mice compared to wild type, but not significantly (p > 0.05. Thus, innate HSP compensatory responses to oxidative stress are simply insufficient, a result supportive of homeostatic system instability as central to ALS etiology. In vivo aggregate analysis of antioxidant therapy finds SOD1-G93A ALS mouse survival duration significantly increases by 11.2% (p << 0.001 but insignificantly decreases onset age by 2%. Thus, the aggregate antioxidant treatment effect on survival in preclinical ALS is not sufficient to overcome clinical heterogeneity, which explains the literature disparity between preclinical and clinical antioxidant survival benefit. The aggregate effect sizes on preclinical ALS survival and onset illustrate that present antioxidants, alone, are not sufficient to halt ALS, which underscores its multi-factorial nature

  8. The cervical cord in amyotrophic lateral sclerosis. A comparison of the CT-myelography with pathological observation

    International Nuclear Information System (INIS)

    Sugamiya, Hitoshi; Tokumaru, Yukio; Arai, Kimihito; Hirayama, Keizo

    1995-01-01

    The spinal cord with amyotrophic lateral sclerosis was macroscopically examined in five patients using CT-myelography (CTM) and autopsied specimens. The autopsied ages were from 48 to 75 years old (average: 64), and their clinical follow-up periods were from 0.8 to 4.0 years (average: 1.9). Muscular atrophy developed from an upper limb in three patients, whereas from a lower limb in one case and from bulbar muscles in another case. Cervical CTM was performed at C3 to C7 cervical vertebrae less than one year (four cases) and 1.9 years (one case) prior to autopsy. The macroscopical examination of the CTM and autopsied specimens showed the following characteristics: Two patients, whose clinical courses were less than one year from the onset, showed no abnormalities. Three patients, whose clinical courses were more than one year from the onset, showed a marked cervical flattening and concave of the posterolateral fissure, especially at the lower cervical level. It was supposed that this lower cervical abnormalities caused pronounced amyotrophy in the upper limbs and pyramidal tract sign of the lower limbs. Although muscular atrophy was asymmetric in one case, the spinal cord was symmetric in macroscopic appearance in both CTM and autopsied specimens. It was concluded that marked flattening and concave at the posterolateral fissure of the lower cervical spinal cord were revealed by CTM in patients whose clinical courses of amyotrophic lateral sclerosis were more than one year from the onset. (author)

  9. Disruption of TCA Cycle and Glutamate Metabolism Identified by Metabolomics in an In Vitro Model of Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Veyrat-Durebex, Charlotte; Corcia, Philippe; Piver, Eric; Devos, David; Dangoumau, Audrey; Gouel, Flore; Vourc'h, Patrick; Emond, Patrick; Laumonnier, Frédéric; Nadal-Desbarats, Lydie; Gordon, Paul H; Andres, Christian R; Blasco, Hélène

    2016-12-01

    This study aims to develop a cellular metabolomics model that reproduces the pathophysiological conditions found in amyotrophic lateral sclerosis in order to improve knowledge of disease physiology. We used a co-culture model combining the motor neuron-like cell line NSC-34 and the astrocyte clone C8-D1A, with each over-expressing wild-type or G93C mutant human SOD1, to examine amyotrophic lateral sclerosis (ALS) physiology. We focused on the effects of mutant human SOD1 as well as oxidative stress induced by menadione on intracellular metabolism using a metabolomics approach through gas chromatography coupled with mass spectrometry (GC-MS) analysis. Preliminary non-supervised analysis by Principal Component Analysis (PCA) revealed that cell type, genetic environment, and time of culture influenced the metabolomics profiles. Supervised analysis using orthogonal partial least squares discriminant analysis (OPLS-DA) on data from intracellular metabolomics profiles of SOD1 G93C co-cultures produced metabolites involved in glutamate metabolism and the tricarboxylic acid cycle (TCA) cycle. This study revealed the feasibility of using a metabolomics approach in a cellular model of ALS. We identified potential disruption of the TCA cycle and glutamate metabolism under oxidative stress, which is consistent with prior research in the disease. Analysis of metabolic alterations in an in vitro model is a novel approach to investigation of disease physiology.

  10. The cervical cord in amyotrophic lateral sclerosis. A comparison of the CT-myelography with pathological observation

    Energy Technology Data Exchange (ETDEWEB)

    Sugamiya, Hitoshi; Tokumaru, Yukio; Arai, Kimihito; Hirayama, Keizo [Chiba Univ. (Japan). School of Medicine

    1995-08-01

    The spinal cord with amyotrophic lateral sclerosis was macroscopically examined in five patients using CT-myelography (CTM) and autopsied specimens. The autopsied ages were from 48 to 75 years old (average: 64), and their clinical follow-up periods were from 0.8 to 4.0 years (average: 1.9). Muscular atrophy developed from an upper limb in three patients, whereas from a lower limb in one case and from bulbar muscles in another case. Cervical CTM was performed at C3 to C7 cervical vertebrae less than one year (four cases) and 1.9 years (one case) prior to autopsy. The macroscopical examination of the CTM and autopsied specimens showed the following characteristics: Two patients, whose clinical courses were less than one year from the onset, showed no abnormalities. Three patients, whose clinical courses were more than one year from the onset, showed a marked cervical flattening and concave of the posterolateral fissure, especially at the lower cervical level. It was supposed that this lower cervical abnormalities caused pronounced amyotrophy in the upper limbs and pyramidal tract sign of the lower limbs. Although muscular atrophy was asymmetric in one case, the spinal cord was symmetric in macroscopic appearance in both CTM and autopsied specimens. It was concluded that marked flattening and concave at the posterolateral fissure of the lower cervical spinal cord were revealed by CTM in patients whose clinical courses of amyotrophic lateral sclerosis were more than one year from the onset. (author).

  11. The severity of respiratory disorders in different forms of amyotrophic lateral sclerosis

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    Yu. N. Rushkevich

    2017-01-01

    Full Text Available Sleep-disordered breathing (SDB substantially impairs quality of life in a patient with amyotrophic lateral sclerosis (ALS and promote the addition of serious respiratory and cardiovascular complications.Objective: to identify the early signs of SDB in patients with various onset ALS using a comprehensive sleep assessment.Patients and methods. A questionnaire survey using a comprehensive test for sleep disorders was conducted in 65 patients: 39 of them had ALS (male:female ratio, 25:14; age, 59 [51; 66] years and 26 patients made up a control group (male:female ratio, 13:13; age, 54 [43; 59] years.The questionnaire consists of 50 questions; the results were expressed as scores.Screening portable polysomnographic study was conducted in patients with newly diagnosed ALS at the relatively early stages of the disease.A total of 61 patients (32 women and 29 men; median (Me and the 25th and 75th percentile age was 62 [55; 67] years were examined. The disease duration was 12 [8.9, 27.1] months after the onset of the first symptoms. The body mass index was 25.7 [23.3, 28.7] kg/m2 . In the studygroup, ALSFRSR [9] scores at study inclusion were 34.32 [32; 38]. Cervicothoracic onset ALS was present in 23 patients; 26 and 12 patients had bulbar and lumbosacral onsets, respectively.Screening diagnosis of sleep was carried out using a Polymate YH-1000C portable polysomnograph (BMC, China that registered nasopharyngeal flow (airflow through the nasal and oral cavities; thoracoabdominal movements (movements of the thoracic and abdominal walls; hemoglobin oxygen saturation of arterial blood ( SpO2; a snore sound through the microphone; and sleeping position (actography.Results. The comprehensive screening study of breathing during sleep shows the underestimation of the complaints and symptoms of subclinical respiratory disorders in patients with ALS. Portable pulse oximetry at the early stages of the disease revealed changes in the nocturnal respiratory

  12. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van Es, Michael A.; Veldink, Jan H.; Saris, Christiaan G. J.; Blauw, Hylke M.; van Vught, Paul W. J.; Birve, Anna; Lemmens, Robin; Schelhaas, Helenius J.; Groen, Ewout J. N.; Huisman, Mark H. B.; van der Kooi, Anneke J.; de Visser, Marianne; Dahlberg, Caroline; Estrada, Karol; Rivadeneira, Fernando; Hofman, Albert; Zwarts, Machiel J.; van Doormaal, Perry T. C.; Rujescu, Dan; Strengman, Eric; Giegling, Ina; Muglia, Pierandrea; Tomik, Barbara; Slowik, Agnieszka; Uitterlinden, Andre G.; Hendrich, Corinna; Waibel, Stefan; Meyer, Thomas; Ludolph, Albert C.; Glass, Jonathan D.; Purcell, Shaun; Cichon, Sven; Nöthen, Markus M.; Wichmann, H.-Erich; Schreiber, Stefan; Vermeulen, Sita H. H. M.; Kiemeney, Lambertus A.; Wokke, John H. J.; Cronin, Simon; McLaughlin, Russell L.; Hardiman, Orla; Fumoto, Katsumi; Pasterkamp, R. Jeroen; Meininger, Vincent; Melki, Judith; Leigh, P. Nigel; Shaw, Christopher E.; Landers, John E.; Al-Chalabi, Ammar; Brown, Robert H.; Robberecht, Wim; Andersen, Peter M.; Ophoff, Roel A.; van den Berg, Leonard H.

    2009-01-01

    We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P <1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide

  13. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study.

    LENUS (Irish Health Repository)

    Byrne, Susan

    2012-03-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons, associated with frontotemporal dementia (FTD) in about 14% of incident cases. We assessed the frequency of the recently identified C9orf72 repeat expansion in familial and apparently sporadic cases of ALS and characterised the cognitive and clinical phenotype of patients with this expansion.

  14. The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

    DEFF Research Database (Denmark)

    Lill, Christina M; Rengmark, Aina; Pihlstrøm, Lasse

    2015-01-01

    A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we...

  15. Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones

    NARCIS (Netherlands)

    Highley, J. Robin; Kirby, Janine; Jansweijer, Joeri A.; Webb, Philip S.; Hewamadduma, Channa A.; Heath, Paul R.; Higginbottom, Adrian; Raman, Rohini; Ferraiuolo, Laura; Cooper-Knock, Johnathan; McDermott, Christopher J.; Wharton, Stephen B.; Shaw, Pamela J.; Ince, Paul G.

    2014-01-01

    Loss of nuclear TDP-43 characterizes sporadic and most familial forms of amyotrophic lateral sclerosis (ALS). TDP-43 (encoded by TARDBP) has multiple roles in RNA processing. We aimed to determine whether (1) RNA splicing dysregulation is present in lower motor neurones in ALS and in a motor

  16. Expression of the low affinity neurotrophin receptor p75 in spinal motoneurons in a transgenic mouse model for amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Copray, JCVM; Jaarsma, D; Kust, BM; Bruggeman, RWG; Mantingh, [No Value; Brouwer, N; Boddeke, HWGM

    2003-01-01

    Amyotrophic lateral sclerosis is a lethal neurodegenerative disorder involving motoneuron loss in the cortex, brainstem and spinal cord, resulting in progressive paralysis. Aberrant neurotrophin signalling via the low affinity neurotrophin receptor p75 has been suggested to be involved in the

  17. FET Proteins TAF15 and EWS Are Selective Markers that Distinguish FTLD with FUS Pathology from Amyotrophic Lateral Sclerosis with "FUS" Mutations

    Science.gov (United States)

    Neumann, Manuela; Bentmann, Eva; Dormann, Dorothee; Jawaid, Ali; DeJesus-Hernandez, Mariely; Ansorge, Olaf; Roeber, Sigrun; Kretzschmar, Hans A.; Munoz, David G.; Kusaka, Hirofumi; Yokota, Osamu; Ang, Lee-Cyn; Bilbao, Juan; Rademakers, Rosa; Haass, Christian; Mackenzie, Ian R. A.

    2011-01-01

    Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in "FUS" as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with "FUS" mutations. The mechanisms…

  18. Clinical features and lifestyle of patients with amyotrophic lateral sclerosis in Campania: brief overview of an Italian database

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    Francesca Trojsi

    2012-01-01

    Full Text Available BACKGROUND: Physical activity and occupational exposures appeared to play a relevant role in pathogenesis of amyotrophic lateral sclerosis (ALS, a neurodegenerative disease of unknown origin. MATERIALS AND METHODS: We aimed to make an overview of the clinical characteristics and lifestyle (occupation and sport of a population of 395 patients with ALS from Campania, in southern Italy. RESULTS: ALS onset resulted anticipated of about 11 years in industry workers, whilst the more frequent site of onset among farmers was upper limbs. Compared to non-athletes, athletes, particularly soccer players, showed a 7 years anticipation of ALS onset, with higher mortality after 5 years. DISCUSSION AND CONCLUSIONS: We suggest that subjects genetically prone to abnormal response to hypoxia during strenuous physical activity or exposed to neurotoxic agents, such as athletes, farmers or industry workers, might present increased risk to develop ALS. Future case-control and follow-up studies on our population should be implemented to deepen the present results.

  19. The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine

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    Erin C. Hedges

    2016-01-01

    Full Text Available In recent years several genes have linked amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD as a spectrum disease; however little is known about what triggers their onset. With the ability to generate patient specific stem cell lines from somatic cells, it is possible to model disease without the need to transfect cells with exogenous DNA. These pluripotent stem cells have opened new avenues for identification of disease phenotypes and their relation to specific molecular pathways. Thus, as never before, compounds with potential applications for regenerative medicine can be specifically tailored in patient derived cultures. In this review, we discuss how patient specific induced pluripotent stem cells (iPSCs have been used to model ALS and FTD and the most recent drug screening targets for these diseases. We also discuss how an iPSC bank would improve the quality of the available cell lines and how it would increase knowledge about the ALS/FTD disease spectrum.

  20. Usefulness of diffusion tensor imaging in amyotrophic lateral sclerosis: potential biomarker and association with the cognitive profile

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    Marcelo Chaves

    Full Text Available ABSTRACT The objective of this preliminary study was to correlate diffusion tensor imaging (DTI alterations with the cognitive profile of patients with amyotrophic lateral sclerosis (ALS. Methods This was a case-control study conducted from December 1, 2012 to December 1, 2014. Clinical and demographic data were recorded. A neuropsychological test battery adapted to ALS patients was used. An MRI with DTI was performed in all patients and fractional anisotropy (FA was analyzed in the white matter using the tract based spatial statistics program. Results Twenty-four patients with ALS (15 females, mean age 66.9 + -2.3 and 13 healthy controls (four females, average age 66.9 + - 2 were included. The DTI showed white matter damage in ALS patients vs. healthy controls (p < 0.001. Discussion In our preliminary study the alterations of white matter in DTI were significantly associated with cognitive impairment in patients with ALS.

  1. Screening of the transcriptional regulatory regions of vascular endothelial growth factor receptor 2 (VEGFR2 in amyotrophic lateral sclerosis

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    Hartley Judith

    2007-04-01

    Full Text Available Abstract Background Vascular endothelial growth factor (VEGF has neurotrophic activity which is mediated by its main agonist receptor, VEGFR2. Dysregulation of VEGF causes motor neurone degeneration in a mouse model of amyotrophic lateral sclerosis (ALS, and expression of VEGFR2 is reduced in motor neurones and spinal cord of patients with ALS. Methods We have screened the promoter region and 4 exonic regions of functional significance of the VEGFR2 gene in a UK population of patients with ALS, for mutations and polymorphisms that may affect expression or function of this VEGF receptor. Results No mutations were identified in the VEGFR2 gene. We found no association between polymorphisms in the regulatory regions of the VEGFR2 gene and ALS. Conclusion Mechanisms other than genetic variation may downregulate expression or function of the VEGFR2 receptor in patients with ALS.

  2. Spontaneous activity in electromyography may differentiate certain benign lower motor neuron disease forms from amyotrophic lateral sclerosis.

    Science.gov (United States)

    Jokela, Manu E; Jääskeläinen, Satu K; Sandell, Satu; Palmio, Johanna; Penttilä, Sini; Saukkonen, Annamaija; Soikkeli, Raija; Udd, Bjarne

    2015-08-15

    There is limited data on electromyography (EMG) findings in other motor neuron disorders than amyotrophic lateral sclerosis (ALS). We assessed whether the distribution of active denervation detected by EMG, i.e. fibrillations and fasciculations, differs between ALS and slowly progressive motor neuron disorders. We compared the initial EMG findings of 43 clinically confirmed, consecutive ALS patients with those of 41 genetically confirmed Late-onset Spinal Motor Neuronopathy and 14 Spinal and Bulbar Muscular Atrophy patients. Spontaneous activity was more frequently detected in the first dorsal interosseus and deltoid muscles of ALS patients than in patients with the slowly progressive motor neuron diseases. The most important observation was that absent fibrillations in the first dorsal interosseus muscle identified the benign forms with sensitivities of 66%-77% and a specificity of 93%. The distribution of active denervation may help to separate ALS from mimicking disorders at an early stage. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis – A Controversial Role of Protein Disulphide Isomerase

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    Merja eJaronen

    2014-12-01

    Full Text Available Accumulation of proteins in aberrant conformation occurs in many neurodegenerative diseases. Furthermore, dysfunctions in protein handling in endoplasmic reticulum (ER and the following ER stress have been implicated in a vast number of diseases, such as amyotrophic lateral sclerosis (ALS. During excessive ER stress unfolded protein response (UPR is activated to return ER to its normal physiological balance. The exact mechanisms of protein misfolding, accumulation and the following ER stress could lead to neurodegeneration and the question whether UPR is a beneficial compensatory mechanism slowing down the neurodegenerative processes are of interest. Protein disulphide isomerase (PDI is a disulfide bond-modulating ER chaperone, which can also facilitate the ER-associated degradation (ERAD of misfolded proteins. In this review we discuss the recent findings of ER stress, UPR and especially the role of PDI in ALS.

  4. Screening of drugs inhibiting in vitro oligomerization of Cu/Zn-superoxide dismutase with a mutation causing amyotrophic lateral sclerosis

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    Itsuki Anzai

    2016-08-01

    Full Text Available Dominant mutations in Cu/Zn-superoxide dismutase (SOD1 gene have been shown to cause a familial form of amyotrophic lateral sclerosis (SOD1-ALS. A major pathological hallmark of this disease is abnormal accumulation of mutant SOD1 oligomers in the affected spinal motor neurons. While no effective therapeutics for SOD1-ALS is currently available, SOD1 oligomerization will be a good target for developing cures of this disease. Recently, we have reproduced the formation of SOD1 oligomers abnormally cross-linked via disulfide bonds in a test tube. Using our in vitro model of SOD1 oligomerization, therefore, we screened 640 FDA-approved drugs for inhibiting the oligomerization of SOD1 proteins, and three effective classes of chemical compounds were identified. Those hit compounds will provide valuable information on the chemical structures for developing a novel drug candidate suppressing the abnormal oligomerization of mutant SOD1 and possibly curing the disease.

  5. Association between extremely low-frequency electromagnetic fields occupations and amyotrophic lateral sclerosis: a meta-analysis.

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    Hongjie Zhou

    Full Text Available OBJECTIVES: To estimate the relationship between exposure to extremely low-frequency electromagnetic fields (ELF-EMF and the risk of amyotrophic lateral sclerosis (ALS by a meta-analysis. METHODS: Through searching PubMed databases (or manual searching up to April 2012 using the following keywords: "occupational exposure", "electromagnetic fields" and "amyotrophic lateral sclerosis" or "motor neuron disease", seventeen studies were identified as eligible for this meta-analysis. The associations between ELF-EMF exposure and the ALS risk were estimated based on study design (case-control or cohort study, and ELF-EMF exposure level assessment (job title or job-exposure matrix. The heterogeneity across the studies was tested, as was publication bias. RESULTS: Occupational exposure to ELF-EMF was significantly associated with increased risk of ALS in pooled studies (RR = 1.29, 95%CI = 1.02-1.62, and case-control studies (OR = 1.39, 95%CI = 1.05-1.84, but not cohort studies (RR = 1.16, 95% CI = 0.80-1.69. In sub-analyses, similar significant associations were found when the exposure level was defined by the job title, but not the job-exposure matrix. In addition, significant associations between occupational exposure to ELF-EMF and increased risk of ALS were found in studies of subjects who were clinically diagnosed but not those based on the death certificate. Moderate heterogeneity was observed in all analyses. CONCLUSIONS: Our data suggest a slight but significant ALS risk increase among those with job titles related to relatively high levels of ELF-EMF exposure. Since the magnitude of estimated RR was relatively small, we cannot deny the possibility of potential biases at work. Electrical shocks or other unidentified variables associated with electrical occupations, rather than magnetic-field exposure, may be responsible for the observed associations with ALS.

  6. Engaging in patient decision-making in multidisciplinary care for amyotrophic lateral sclerosis: the views of health professionals

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    Hogden A

    2012-09-01

    Full Text Available Anne Hogden,1 David Greenfield,1 Peter Nugus,1 Matthew C Kiernan21Centre for Clinical Governance Research, Australian Institute of Health Innovation, University of New South Wales, 2Prince of Wales Clinical School, University of New South Wales, and Neuroscience Research Australia, Sydney, New South Wales, AustraliaBackground: The aim of this study was to explore clinician perspectives on patient decision-making in multidisciplinary care for amyotrophic lateral sclerosis (ALS, in an attempt to identify factors influencing decision-making.Methods: Thirty-two health professionals from two specialized multidisciplinary ALS clinics participated in individual and group interviews. Participants came from allied health, medical, and nursing backgrounds. Interviews were audio recorded, and the transcripts were analyzed thematically.Results: Respondents identified barriers and facilitators to optimal timing and quality of decision-making. Barriers related to the patient and the health system. Patient barriers included difficulties accepting the diagnosis, information sources, and the patient-carer relationship. System barriers were timing of diagnosis and symptom management services, access to ALS-specific resources, and interprofessional communication. Facilitators were teamwork approaches, supported by effective communication and evidence-based information.Conclusion: Patient-centered and collaborative decision-making is influenced by a range of factors that inhibit the delivery of optimal care. Decision-making relies on a fine balance between timing of information and service provision, and the readiness of patients to receive them. Health system restrictions impacted on optimal timing, and patients coming to terms with their condition. Clinicians valued proactive decision-making to prepare patients and families for inevitable change. The findings indicate disparity between patient choices and clinician perceptions of evidence, knowledge, and

  7. Conceptualizing the relations between metacognition and executive functions in Amyotrophic Lateral Sclerosis (ALS patients’ caregivers. A preliminary study

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    Stefania La Foresta

    2015-12-01

    Full Text Available Executive Functions are goal-directed neurocognitive processes that allow the management of cognition and behavior. Executive Functions are essential to allow people to set goals, self-monitor, inhibit inappropriate responses, and generally engage in well-planned, flexible, future-oriented behavior. Metacognitive processes, in close alliance with executive functions, are viewed as integral components of awareness and emotional regulation. The influence of metacognition on planning, monitoring and mental flexibility has not been investigated. The aim of this pilot study was to examine the relationship between metacognition and executive functions in Amyotrophic Lateral Sclerosis patient's caregivers. Twenty-two caregivers were evaluated using the following instruments: Metacognition Questionnaire-30 and Wisconsin Card Sorting Test. Data analysis was performed using SPSS for Windows applying correlational analysis (Spearman’s Rho. We founded that total score of metacognition is positive correlated with number of perseverative errors made in Wisconsin (0.75 p<.001. In particular, need to control thoughts is positive correlated with number of perseverative errors (0.78 p<.001. Results could suggest the importance to explore the relationship between metacognitive processes and executive functions in order to cope disease’s changes and optimize the relative daily living management. Providing care to a Amyotrophic Lateral Sclerosis relative may cause feelings of burden, psychological distress, anxiety or depression, in particular in case of dysfunctional metacognitions. So, our future researches will be oriented to explore the relationship between psycopatological symptoms and metacognition and executive functions in ALS’caregivers in order to contain caregiver emotional burden.

  8. Genetics Home Reference: juvenile primary lateral sclerosis

    Science.gov (United States)

    ... Manual Consumer Version: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases Patient Support and Advocacy Resources (3 links) Motor Neurone Disease Association (UK) Muscular Dystrophy Association National ...

  9. Alfa-class prefoldin protein UXT is a novel interacting partner of Amyotrophic Lateral Sclerosis 2 (Als2) protein.

    Science.gov (United States)

    Enunlu, Izzet; Ozansoy, Mehmet; Basak, Ayse Nazlı

    2011-09-30

    Mutations in Als2 gene cause several autosomal recessive forms of motor neuron diseases including Juvenile Amyotrophic Lateral Sclerosis (JALS), Juvenile Primary Lateral Sclerosis (PLSJ) and Infantile-onset Ascending Hereditary Spastic Paralysis (IAHSP). To find novel protein-protein interactions of Als2 protein we performed a yeast two hybrid screen and fished out the Ubiquitously Expressed Transcript (UXT) protein. UXT is a novel gene encoding for an α-class prefoldin type chaperone which acts as a co-activator for various transcriptional factors such as Nf-κB and AR. The interaction between Als2 and UXT was confirmed by co-immunoprecipitation. Co-localization between endogenous Als2 and UXT was mainly found in the cytoplasm of neuronal Neuro2a cells with immunofluorescence microscopy. Cell cycle arrest of Neuro2a cells showed that Als2 and Uxt transcriptional levels are synchronously changing. Our results suggest that Als2 is a binding partner of Uxt and Als2/Uxt interaction could be important for the activation of Nf-κB pathway. These results provides basis for future research to investigate the role of Nf-κB pathway in the development of motor neuron diseases. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. The R of ALSFRS-R: does it really mirror functional respiratory involvement in amyotrophic lateral sclerosis?

    Science.gov (United States)

    Pinto, Susana; de Carvalho, Mamede

    2015-03-01

    Clinical assessment of the respiratory function is critical in amyotrophic lateral sclerosis (ALS). A standardized process is to monitor the respiratory subscore of the revised ALSFRS (RofALSFRS-R). We tested the utility of RofALSFRS-R and its individual questions in evaluating respiratory functionality. Three hundred and fifty-seven consecutive ALS patients were assessed at entry (T0), three and six months later (T1 and T2). ALSFRS and its subscores decayed significantly (p QR1) was found in about 10% of the patients in each period. Between T0 and T1 a significant negative correlation was found between decrease in gait score and QR1 (p = 0.021, r = -0.395) in the subgroup of ALS patients who showed QR1 improvement (n = 34). An improvement in the other respiratory questions was noticed in about 6% of the patients, related to non-invasive ventilation. Possibly, decreased mobility and metabolic demand can cause fewer respiratory symptoms in a subset of patients. The respiratory questions included in ALSFRS-R should be re-addressed by the ALS community.

  11. Quality of life in amyotrophic lateral sclerosis patients and caregivers: Impact of assistive communication from early stages.

    Science.gov (United States)

    Londral, Ana; Pinto, Anabela; Pinto, Susana; Azevedo, Luis; De Carvalho, Mamede

    2015-12-01

    In this study we performed a longitudinal investigation to assess the impact of early introduction of assistive communication devices (ACDs) on quality of life (QoL) in amyotrophic lateral sclerosis (ALS) patients and their caregivers. Patients were followed for 7-10 months (3 evaluation periods). Bulbar-onset ALS patients (N = 27) and paired caregivers (N = 17) were included. Fifteen randomly selected patients received early support in ACD use. Patients were assessed using the ALS Functional Rating Scale-revised (ALSFRS-R), the McGill QoL (MQoL), the Communication Effectiveness Index (CETI), and performance in writing; and caregivers were assessed with the MQoL and World Health Organization Quality of Life questionnaire (WHOQOL-BREF). Patients with early support had higher MQoL Psychological and MQoL Existential well-being domains; caregivers had higher MQoL Support domain and their MQoL Psychological domain positively associated with patient CETI. Most patients could communicate using a touchscreen keyboard to write, even when handwriting and speech were not possible. Early intervention with an ACD seems to have a positive impact on QoL and gives patients the opportunity to improve skills for communication in later disease stages. © 2015 Wiley Periodicals, Inc.

  12. Screening for cognitive and behavioural impairment in amyotrophic lateral sclerosis: Frequency of abnormality and effect on survival.

    Science.gov (United States)

    Xu, Zhouwei; Alruwaili, Ashwag Rafea S; Henderson, Robert David; McCombe, Pamela Ann

    2017-05-15

    To screen for cognitive and behavioural impairment in people with amyotrophic lateral sclerosis (ALS) and controls with neuromuscular disease and to correlate these with clinical features. 108 people with ALS and 60 controls with other neuromuscular diseases were recruited and assessed with the Addenbrooke's cognitive examination-III (ACE-III), the frontal assessment battery (FAB), and the executive function component of the Edinburgh cognitive and behavioural ALS screen (ECAS). The Amyotrophic lateral sclerosis-Frontotemporal dementia questionnaire (ALS-FTD-Q) and the Motor Neuron Disease Behavioural instrument (MiND-B) were administered to the caregivers of people with ALS. The prevalence of abnormalities was determined and correlated with clinical features and survival. In 37 people with ALS, serial studies were performed. The frequencies of cognitive impairment based on the ACE-III and FAB were 30.0% and 14.0%, in ALS and 11.7% and 3.3% in controls, respectively. Age and years of education influence the results of the ACE-III and ECAS executive function. In ALS, the frequencies of behavioural impairment based on ALS-FTD-Q and MiND-B were 32.1% and 39.4%, respectively. There is significant correlation of ALS-FTD-Q and MiND-B with the ALSFRS-R score. ALS participants with cognitive impairment measured with ACE-III had significantly shorter survival time than those without. ALS participants with behavioural impairment measured with ALS-FTD-Q had worse prognosis than those without. No significant difference was found between the first two serial cognitive tests based on ACE-III and FAB by using generalized estimating equation. There is a greater frequency of cognitive impairment in people with ALS than in patients with other neuromuscular diseases. The cognitive and behavioural tests are potential biomarkers of the prognosis of ALS. The results of cognitive tests are stable over 6months and possibly longer. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. CACNA1H missense mutations associated with amyotrophic lateral sclerosis alter Ca(v)3.2 T-type calcium channel activity and reticular thalamic neuron firing

    Czech Academy of Sciences Publication Activity Database

    Rzhepetskyy, Yuriy; Lazniewska, Joanna; Blesneac, I.; Pamphlett, R.; Weiss, Norbert

    2016-01-01

    Roč. 10, č. 6 (2016), s. 466-477 ISSN 1933-6950 R&D Projects: GA ČR GA15-13556S; GA MŠk 7AMB15FR015 Institutional support: RVO:61388963 Keywords : ALS * amyotrophic lateral sclerosis * biophysics * CACNA1H * Ca(v)3 * 2 channel Subject RIV: CE - Biochemistry Impact factor: 2.042, year: 2016

  14. Immunoglobulins G from Sera of Amyotrophic Lateral Sclerosis Patients Induce Oxidative Stress and Upregulation of Antioxidative System in BV-2 Microglial Cell Line

    OpenAIRE

    Milošević, Milena; Milićević, Katarina; Božić, Iva; Lavrnja, Irena; Stevanović, Ivana; Bijelić, Dunja; Dubaić, Marija; Živković, Irena; Stević, Zorica; Giniatullin, Rashid; Andjus, Pavle

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with a very fast progression, no diagnostic tool for the presymptomatic phase, and still no effective treatment of the disease. Although ALS affects motor neurons, the overall pathophysiological condition points out to the non-cell autonomous mechanisms, where astrocytes and microglia play crucial roles in the disease progression. We have already shown that IgG from sera of ALS patients (ALS IgG) induce calcium transients and...

  15. Post activation depression of the Ia EPSP in motoneurones is reduced in both aged mice and in the G127X SOD1 model of Amyotrophic lateral sclerosis

    DEFF Research Database (Denmark)

    Hedegaard, Anne; Lehnhoff, Janna; Moldovan, Mihai

    2014-01-01

    D in both normal aging and in the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). We used both wild type (WT) C57BL/6J mice and the G127X SOD1 transgenic model of ALS (Jonsson et al 2004)Mice were anaesthetized with Hypnorm (0.315mg/mL fentanyl-citrate +10mg/mL fluanisone), Midazolam (5mg...

  16. Wnt Signaling Alteration in the Spinal Cord of Amyotrophic Lateral Sclerosis Transgenic Mice: Special Focus on Frizzled-5 Cellular Expression Pattern.

    Directory of Open Access Journals (Sweden)

    Carlos González-Fernández

    Full Text Available Amyotrophic lateral sclerosis is a chronic neurodegenerative disease characterized by progressive paralysis due to degeneration of motor neurons by unknown causes. Recent evidence shows that Wnt signaling is involved in neurodegenerative processes, including Amyotrophic Lateral Sclerosis. However, to date, little is known regarding the expression of Wnt signaling components in this fatal condition. In the present study we used transgenic SOD1G93A mice to evaluate the expression of several Wnt signaling components, with special focus on Frizzled-5 cellular expression alteration along disease progression.Based on previous studies demonstrating the expression of Wnts and their transcriptional regulation during Amyotrophic lateral sclerosis development, we have analyzed the mRNA expression of several Wnt signaling components in the spinal cord of SOD1G93A transgenic mice at different stages of the disease by using real time quantitative PCR analysis. Strikingly, one of the molecules that seemed not to be altered at mRNA level, Frizzled-5, showed a clear up-regulation at late stages in neurons, as evidenced by immunofluorescence assays. Moreover, increased Frizzled-5 appears to correlate with a decrease in NeuN signal in these cells, suggesting a correlation between neuronal affectation and the increased expression of this receptor.Our data suggest the involvement of Wnt signaling pathways in the pathophysiology of Amyotrophic Lateral Sclerosis and, more specifically, the implication of Frizzled-5 receptor in the response of neuronal cells against neurodegeneration. Nevertheless, further experimental studies are needed to shed light on the specific role of Frizzled-5 and the emerging but increasing Wnt family of proteins research field as a potential target for this neuropathology.

  17. 26Al tracer experiment by accelerator mass spectrometry and its application to the studies for amyotrophic lateral sclerosis and Alzheimer's disease, 1

    International Nuclear Information System (INIS)

    Kobayashi, Koichi; Yumoto, Sakae; Nagai, Hisao; Hosoyama, Yoshiyuki; Imamura, Mineo; Masuzawa, Shin-ichirou; Koizumi, Yoshinobu; Yamashita, Hiroshi.

    1990-01-01

    Accelerator mass spectrometry (AMS) was applied for 26 Al tracer experiment to study the aluminum toxicity and metabolism in rats. To investigate the cause of amyotrophic lateral sclerosis (ALS) and Alzheimer's disease, the aluminum incorporation into the brain (cerebrum) was studied by AMS using 26 Al as a tracer. When 26 Al was intraperitoneally injected into rats, a considerable amount of 26 Al was incorporated into the cerebrum after 5-35 days of the injection. (author)

  18. The anti-inflammatory peptide stearyl-norleucine-VIP delays disease onset and extends survival in a rat model of inherited amyotrophic lateral sclerosis.

    Science.gov (United States)

    Goursaud, Stéphanie; Schäfer, Sabrina; Dumont, Amélie O; Vergouts, Maxime; Gallo, Alessandro; Desmet, Nathalie; Deumens, Ronald; Hermans, Emmanuel

    2015-01-01

    Vasoactive intestinal peptide (VIP) has potent immune modulatory actions that may influence the course of neurodegenerative disorders associated with chronic inflammation. Here, we show the therapeutic benefits of a modified peptide agonist stearyl-norleucine-VIP (SNV) in a transgenic rat model of amyotrophic lateral sclerosis (mutated superoxide dismutase 1, hSOD1(G93A)). When administered by systemic every-other-day intraperitoneal injections during a period of 80 days before disease, SNV delayed the onset of motor dysfunction by no less than three weeks, while survival was extended by nearly two months. SNV-treated rats showed reduced astro- and microgliosis in the lumbar ventral spinal cord and a significant degree of motor neuron preservation. Throughout the treatment, SNV promoted the expression of the anti-inflammatory cytokine interleukin-10 as well as neurotrophic factors commonly considered as beneficial in amyotrophic lateral sclerosis management (glial derived neuroptrophic factor, insulin like growth factor, brain derived neurotrophic factor). The peptide nearly totally suppressed the expression of tumor necrosis factor-α and repressed the production of the pro-inflammatory mediators interleukin-1β, nitric oxide and of the transcription factor nuclear factor kappa B. Inhibition of tumor necrosis factor-α likely accounted for the observed down-regulation of nuclear factor kappa B that modulates the transcription of genes specifically involved in amyotrophic lateral sclerosis (sod1 and the glutamate transporter slc1a2). In line with this, levels of human superoxide dismutase 1 mRNA and protein were decreased by SNV treatment, while the expression and activity of the glutamate transporter-1 was promoted. Considering the large diversity of influences of this peptide on both clinical features of the disease and associated biochemical markers, we propose that SNV or related peptides may constitute promising candidates for amyotrophic lateral sclerosis

  19. S-Nitrosoglutathione Reductase Plays Opposite Roles in SH-SY5Y Models of Parkinson's Disease and Amyotrophic Lateral Sclerosis

    OpenAIRE

    Rizza, Salvatore; Cirotti, Claudia; Montagna, Costanza; Cardaci, Simone; Consales, Claudia; Cozzolino, Mauro; Carrì, Maria Teresa; Cecconi, Francesco; Filomeni, Giuseppe

    2015-01-01

    Oxidative and nitrosative stresses have been reported as detrimental phenomena concurring to the onset of several neurodegenerative diseases. Here we reported that the ectopic modulation of the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR) differently impinges on the phenotype of two SH-SY5Y-based in vitro models of neurodegeneration, namely, Parkinson’s disease (PD) and familial amyotrophic lateral sclerosis (fALS). In particular, we provide evidence that GSNOR-knocking down ...

  20. Automobile or other conveyance and adaptive equipment certificate of eligibility for veterans or members of the armed forces with amyotrophic lateral sclerosis. Interim final rule.

    Science.gov (United States)

    2015-02-25

    The Department of Veterans Affairs (VA) is amending its adjudication regulation regarding certificates of eligibility for financial assistance in the purchase of an automobile or other conveyance and adaptive equipment. The amendment authorizes automatic issuance of a certificate of eligibility for financial assistance in the purchase of an automobile or other conveyance and adaptive equipment to all veterans with service-connected amyotrophic lateral sclerosis (ALS) and members of the Armed Forces serving on active duty with ALS.

  1. Prospective Validation of 18F-FDG Brain PET Discriminant Analysis Methods in the Diagnosis of Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Van Weehaeghe, Donatienne; Ceccarini, Jenny; Delva, Aline; Robberecht, Wim; Van Damme, Philip; Van Laere, Koen

    2016-08-01

    An objective biomarker for early identification and accurate differential diagnosis of amyotrophic lateral sclerosis (ALS) is lacking. (18)F-FDG PET brain imaging with advanced statistical analysis may provide a tool to facilitate this. The objective of this work was to validate volume-of-interest (VOI) and voxel-based (using a support vector machine [SVM] approach) (18)F-FDG PET analysis methods to differentiate ALS from controls in an independent prospective large cohort, using a priori-derived classifiers. Furthermore, the prognostic value of (18)F-FDG PET was evaluated. A prospective cohort of patients with a suspected diagnosis of a motor neuron disorder (n = 119; mean age ± SD, 61 ± 12 y; 81 men and 38 women) was recruited. One hundred five patients were diagnosed with ALS (mean age ± SD, 61.0 ± 12 y; 74 men and 31 women) (group 2), 10 patients with primary lateral sclerosis (mean age ± SD, 55.5 ± 12 y; 3 men and 7 women), and 4 patients with progressive muscular atrophy (mean age ± SD, 59.2 ± 5 y; 4 men). The mean disease duration of all patients was 15.0 ± 13.4 mo at diagnosis, with PET conducted 15.2 ± 13.3 mo after the first symptoms. Data were compared with a previously gathered dataset of 20 screened healthy subjects (mean age ± SD, 62.4 ± 6.4 y; 12 men and 8 women) and 70 ALS patients (mean age ± SD, 62.2 ± 12.5 y; 44 men and 26 women) (group 1). Data were spatially normalized and analyzed on a VOI basis (statistical software (using the Hammers atlas) and voxel basis using statistical parametric mapping. Discriminant analysis and SVM were used to classify new cases based on the classifiers derived from group 1. Compared with controls, ALS patients showed a nearly identical pattern of hypo- and hypermetabolism in groups 1 and 2. VOI-based discriminant analysis resulted in an 88.8% accuracy in predicting the new ALS cases. For the SVM approach, this accuracy was 100%. Brain metabolism between ALS and primary lateral sclerosis patients was

  2. Adipokines, C-reactive protein and Amyotrophic Lateral Sclerosis - results from a population- based ALS registry in Germany.

    Science.gov (United States)

    Nagel, Gabriele; Peter, Raphael S; Rosenbohm, Angela; Koenig, Wolfgang; Dupuis, Luc; Rothenbacher, Dietrich; Ludolph, Albert C

    2017-06-29

    To investigate the associations of leptin, adiponectin and high-sensitive (hs) C-reactive protein (CRP) with risk and prognosis of amyotrophic lateral sclerosis (ALS). Data from a population-based case-control study in Southern Germany (10/2010-6/2014) of 289 ALS patients (mean age of 65.7 (SD 10.5) years, 59.5% men) and 506 controls were included. During median follow-up of 14.5 months of 279 ALS patients 104 (53.9% men, 68.9 (10.3) years) died. Serum samples were measured for leptin, adiponectin and hs-CRP. Conditional logistic regression was used to estimate ALS risk. Survival models were used to appraise the prognostic value. ALS patients were characterized by lower levels of school education, BMI and smoking prevalence. Adjusted for covariates, leptin was inversely associated with ALS risk (top vs. bottom quartile: OR 0.49; 95% CI 0.29-0.80), while for adiponectin a positive association was found (OR 2.89; 95% CI 1.78-4.68). Among ALS patients increasing leptin concentrations were associated with longer survival (p for trend 0.002), while for adiponectin no association was found (p for trend 0.55). For hs-CRP no association was found. Leptin and adiponectin, two key hormones regulating energy metabolism, were strongly and independently related with ALS risk. Leptin levels were further negatively related with overall survival of ALS patients.

  3. Studies of Environmental Risk Factors in Amyotrophic Lateral Sclerosis (ALS) and a Phase I Clinical Trial of L-Serine.

    Science.gov (United States)

    Bradley, Walter G; Miller, R X; Levine, T D; Stommel, E W; Cox, P A

    2018-01-01

    β-N-Methylamino-L-alanine (BMAA) has been linked to Guam ALS/PDC and shown to produce neurodegeneration in vitro and in vivo (Drosophila, mice, rats, primates). BMAA misincorporation into neuroproteins produces protein misfolding and is inhibited by L-serine. Case-control studies in Northern New England indicate that living near to water-bodies with cyanobacterial blooms increases the risk of developing amyotrophic lateral sclerosis (ALS). The distribution of addresses of ALS cases in New Hampshire, Vermont, and Florida was compared to that of controls. Areas of statistically significantly increased numbers of ALS cases were examined for sources of environmental toxins. A phase I trial of oral L-serine was performed in 20 ALS patients (0.5 to 15 g twice daily). Safety and tolerability were assessed by comparing the rate of deterioration with 430 matched placebo controls. The distribution of residential addresses of ALS cases in New England and Florida revealed many areas where the age- and gender-adjusted frequency of ALS was greater than expected (P ALS patients suggests that residential exposure to environmental pollutants may play an important role in the etiology of ALS. L-Serine in doses up to 15 g twice daily appears to be safe in patients with ALS. Exploratory studies of efficacy suggested that L-serine might slow disease progression. A phase II trial is planned.

  4. Physical and cognitive fitness in young adulthood and risk of amyotrophic lateral sclerosis at an early age.

    Science.gov (United States)

    Longinetti, E; Mariosa, D; Larsson, H; Almqvist, C; Lichtenstein, P; Ye, W; Fang, F

    2017-01-01

    There is a clinical impression that patients with amyotrophic lateral sclerosis (ALS) have a higher level of physical fitness and lower body mass index (BMI) than average. However, there is a lack of literature examining the relationship between cognitive fitness and ALS risk. In this study we explored the associations of both physical and cognitive fitness with future risk of ALS. Data on physical fitness, BMI, intelligence quotient (IQ) and stress resilience were collected from 1 838 376 Swedish men aged 17-20 years at conscription during 1968-2010. Their subsequent ALS diagnoses were identified through the Swedish Patient Register. Hazard ratios (HRs) and 95% CIs from flexible parametric models were used to assess age-specific associations of physical fitness, BMI, IQ and stress resilience with ALS. We identified 439 incident ALS cases during follow-up (mean age at diagnosis: 48 years). Individuals with physical fitness above the highest tertile tended to have a higher risk of ALS before the age of 45 years (range of HRs: 1.42-1.75; statistically significant associations at age 41-43 years) compared with others. Individuals with BMI ≥ 25 tended to have a lower risk of ALS at all ages (range of HRs: 0.42-0.80; statistically significant associations at age 42-48 years) compared with those with BMI Physical fitness, BMI, IQ and stress resilience in young adulthood might be associated with the development of ALS at an early age. © 2016 EAN.

  5. Profile of medical care costs in patients with amyotrophic lateral sclerosis in the Medicare programme and under commercial insurance.

    Science.gov (United States)

    Meng, Lisa; Bian, Amy; Jordan, Scott; Wolff, Andrew; Shefner, Jeremy M; Andrews, Jinsy

    2018-02-01

    To determine amyotrophic lateral sclerosis (ALS)-associated costs incurred by patients covered by Medicare and/or commercial insurance before, during and after diagnosis and provide cost details. Costs were calculated from the Medicare Standard Analytical File 5% sample claims data from Parts A and B from 2009, 2010 and 2011 for ALS Medicare patients aged ≥70 years (monthly costs) and ≥65 years (costs associated with disability milestones). Commercial insurance patients aged 18-63 years were selected based on the data provided in the Coordination of Benefits field from Truven MarketScan® in 2008-2010. Monthly costs increased nine months before diagnosis, peaked during the index month (Medicare: $10,398; commercial: $9354) and decreased but remained high post-index. Costs generally shifted from outpatient to inpatient and private nursing after diagnosis; prescriptions and durable medical equipment costs were much higher for commercial patients post-diagnosis. Patients appeared to progress to disability milestones more rapidly as their disease progressed in severity (14.4 months to non-invasive ventilation [NIV] vs. 16.6 months to hospice), and their costs increased accordingly (NIV: $58,973 vs. hospice: $76,179). For newly diagnosed ALS patients in the U.S., medical costs are substantial and increase rapidly and substantially with each disability milestone.

  6. A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement.

    Science.gov (United States)

    Macchi, Zachary; Wang, Yunxia; Moore, Dan; Katz, Jonathan; Saperstein, David; Walk, David; Simpson, Ericka; Genge, Angela; Bertorini, Tulio; Fernandes, J Americo; Swenson, Andrea; Elman, Lauren; Dimachkie, Mazen; Herbelin, Laura; Miller, Joann; Lu, Jianghua; Wilkins, Heather; Swerdlow, Russell H; Statland, Jeffrey; Barohn, Richard

    2015-01-01

    Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, p = 0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, p < 0.0001). In conclusion, engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial.

  7. A Complex Network of MicroRNAs Expressed in Brain and Genes Associated with Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Santosh Shinde

    2013-01-01

    Full Text Available Amyotrophic Lateral Sclerosis (ALS is a rare neurological disease affecting mainly motor neurons and often leads to paralysis and death in extreme cases. For exploring the role of microRNAs in genes regulation in ALS disease, miRanda was employed for prediction of target sites of miRNAs expressed in various parts of brain and CNS on 35 genes associated with ALS. Similar search was conducted using TargetScan and PicTar for prediction of target sites in 3′ UTR only. 1456 target sites were predicted using miRanda and more target sites were found in 5′ UTR and CDS region as compared to 3′ UTR. 11 target sites were predicted to be common by all the algorithms and, thus, these represent the most significant sites. Target site hotspots were identified and were recognized as hotspots for multiple miRNAs action, thus, acting as favoured sites of action for the repression of gene expression. The complex interplay of genes and miRNAs brought about by multiplicity and cooperativity was explored. This investigation will aid in elucidating the mechanism of action of miRNAs for the considered genes. The intrinsic network of miRNAs expressed in nervous system and genes associated with ALS may provide rapid and effective outcome for therapeutic applications and diagnosis.

  8. Iyengar yoga therapy as an intervention for cramp management in individuals with amyotrophic lateral sclerosis: three case reports.

    Science.gov (United States)

    Ribeiro, Subbappa

    2014-04-01

    Patients with amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of motor neurons, experience cramps at all stages of the illness. There is, at present, no effective medication to control the cramps and no agreement on how to treat the symptom in ALS patients. Three individuals who were diagnosed with ALS and reported suffering cramps in various parts of the body, which limited their activities or affected their sleep were invited to try Iyengar yoga. Yoga therapy, composed of stretching, breathing, and relaxation exercises, was prescribed for each case, based on the subject's physical disability and the presence of other symptoms. Although two subjects experienced cramps during the first therapy session, all three subjects reported the complete cessation of cramping within 3 weeks to 8 weeks of therapy. One of the subjects developed cramps in the hand after discontinuing yoga therapy for 7 months. However, the symptom stopped within 2 weeks of resuming yoga therapy. The alleviation of cramps in these three subjects indicates the possibility of yogic intervention for the management of cramps in individuals with ALS, but further research is necessary to understand the effectiveness of yoga therapy and to determine the exercises that are more prone to lead to cramping in some ALS individuals.

  9. Cellular changes in motor neuron cell culture produced by cytotoxic cerebrospinal fluid from patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Gomez-Pinedo, U; Yáñez, M; Matías-Guiu, J; Galán, L; Guerrero-Sola, A; Benito-Martin, M S; Vela, A; Arranz-Tagarro, J A; García, A G

    2014-01-01

    The neurotoxic effects of cerebrospinal fluid (CSF) from patients with amyotrophic lateral sclerosis (ALS) have been reported by various authors who have attributed this neurotoxicity to the glutamate in CSF-ALS. Cultures of rat embryonic cortical neurons were exposed to CSF from ALS patients during an incubation period of 24 hours. Optical microscopy was used to compare cellular changes to those elicited by exposure to 100μm glutamate, and confocal microscopy was used to evaluate immunohistochemistry for caspase-3, TNFα, and peripherin. In the culture exposed to CSF-ALS, we observed cells with nuclear fragmentation and scarce or null structural modifications to the cytoplasmic organelles or to plasma membrane maintenance. This did not occur in the culture exposed to glutamate. The culture exposed to CSF-ALS also demonstrated increases in caspase-3, TNFα, and in peripherin co-locating with caspase-3, but not with TNFα, suggesting that TNFα may play an early role in the process of apoptosis. CFS-ALS cytotoxicity is not related to glutamate. It initially affects the nucleus without altering the cytoplasmic membrane. It causes cytoplasmic apoptosis that involves an increase in caspase-3 co-located with peripherin, which is also overexpressed. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  10. Theory of Mind and its neuropsychological and Quality of Life correlates in the early stages of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Francesca Trojsi

    2016-12-01

    Full Text Available This study aims to explore the potential impairment of Theory of Mind (ToM (i.e., the ability to represent cognitive and affective mental states to both self and others and the clinical, neuropsychological and Quality of Life (QoL correlates of these cognitive abnormalities in the early stages of amyotrophic lateral sclerosis (ALS, a multisystem neurodegenerative disease recently recognized as a part of the same clinical and pathological spectrum of frontotemporal lobar degeneration.Twenty-two consecutive, cognitively intact ALS patients, and 15 healthy controls, underwent assessment of executive, verbal comprehension, visuospatial, behavioural and QoL measures, as well as of the ToM abilities by Emotion Attribution Task (EAT, Advanced Test of ToM (ATT and Eyes Task (ET.ALS patients obtained significantly lower scores than controls on EAT and ET. No significant difference was found between the two groups on ATT. As regard to type of ALS onset, patients with bulbar onset performed worse than those with spinal onset on ET. Correlation analysis revealed that EAT and ET were positively correlated with education, memory prose, visuo-spatial performances and Mental Health scores among QoL items.Our results suggest that not only cognitive but also affective subcomponents of ToM may be impaired in the early stages of ALS, with significant linkage to disease onset and dysfunctions of less executively demanding conditions, causing potential impact on patients' Mental Health.

  11. Exposure to Environmental Toxicants and Pathogenesis of Amyotrophic Lateral Sclerosis: State of the Art and Research Perspectives

    Directory of Open Access Journals (Sweden)

    Maria Rosaria Monsurrò

    2013-07-01

    Full Text Available There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS, a fatal neuromuscular disease, is caused by gene-environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining percentage of cases. However, relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron degeneration leading to ALS, although exposure to chemicals—including lead and pesticides—agricultural environments, smoking, intense physical activity, trauma and electromagnetic fields have been associated with an increased risk of ALS. This review provides an overview of our current knowledge of potential toxic etiologies of ALS with emphasis on the role of cyanobacteria, heavy metals and pesticides as potential risk factors for developing ALS. We will summarize the most recent evidence from epidemiological studies and experimental findings from animal and cellular models, revealing that potential causal links between environmental toxicants and ALS pathogenesis have not been fully ascertained, thus justifying the need for further research.

  12. The evaluation of bulbar dysfunction in amyotrophic lateral sclerosis: survey of clinical practice patterns in the United States.

    Science.gov (United States)

    Plowman, Emily K; Tabor, Lauren C; Wymer, James; Pattee, Gary

    2017-08-01

    Speech and swallowing impairments are highly prevalent in individuals with amyotrophic lateral sclerosis (ALS) and contribute to reduced quality of life, malnutrition, aspiration, pneumonia and death. Established practice parameters for bulbar dysfunction in ALS do not currently exist. The aim of this study was to identify current practice patterns for the evaluation of speech and swallowing function within participating Northeast ALS clinics in the United States. A 15-item survey was emailed to all registered NEALS centres. Thirty-eight sites completed the survey. The majority (92%) offered Speech-Language Pathology, augmentative and alternative communication (71%), and dietician (92%) health care services. The ALS Functional Rating Scale-Revised and body weight represented the only parameters routinely collected in greater then 90% of responding sites. Referral for modified barium swallow study was routinely utilised in only 27% of sites and the use of percutaneous gastrostomy tubes in ALS patient care was found to vary considerably. This survey reveals significant variability and inconsistency in the management of bulbar dysfunction in ALS across NEALS sites. We conclude that a great need exists for the development of bulbar practice guidelines in ALS clinical care to accurately detect and monitor bulbar dysfunction.

  13. The utility of independent component analysis and machine learning in the identification of the amyotrophic lateral sclerosis diseased brain.

    Directory of Open Access Journals (Sweden)

    Robert C Welsh

    2013-06-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a devastating disease with a lifetime risk of approximately 1 in 2000. Presently diagnosis of ALS relies on clinical assessments for upper motor neuron and lower motor neuron deficits in multiple body segments together with a history of progression of symptoms. In addition, is it common to evaluate lower motor neuron pathology in ALS by electromyography. However, upper motor neuron pathology is solely assessed on clinical grounds hindering diagnosis. In the past decade magnetic resonance methods have been shown to be sensitive to the ALS disease process, namely: resting state connectivity measured with functional MRI, cortical thickness measured by high resolution imaging, diffusion tensor imaging (DTI metrics such as fractional anisotropy (FA and radial diffusivity (RD, and more recently magnet resonance spectroscopy measures of gamma-aminobutyric acid (GABA concentration. In this present work we utilize independent component analysis (ICA to derive brain networks based on resting state functional magnetic resonance imaging and use those derived networks to build a disease state classify using machine learning (support-vector machine. We show that it is possible to achieve over 71% accuracy for disease state classification. These results are promising for the development of a clinically relevant disease state classifier. Future inclusion of other MR modalities such as high resolution derived cortical thickness, DTI metric and MRS should improve this overall accuracy.

  14. Mortality rates due to amyotrophic lateral sclerosis in São Paulo City from 2002 to 2006

    Directory of Open Access Journals (Sweden)

    Sheila Evangelista de Matos

    2011-12-01

    Full Text Available OBJECTIVE: To describe the mortality rates of amyotrophic lateral sclerosis (ALS in the city of São Paulo as a function of demographics, year, and region. METHOD: This was a retrospective descriptive study. Information was obtained from death certificates registered at the Program for the Improvement of Mortality Information, Municipal Health Department (PRO-AIM/SMS, coded as G12.2 according to International Classification of Diseases (ICD-10, from 2002 to 2006. RESULTS: Over the studied time, were found 326 deaths (51.6% women, overall mean age of 64.1 years. Highest deaths percentages happened in those from 60 to 69 and 70 to 79 years and in white individuals. ALS mortality rates ranged 0.44/100,000 in 2002 and 0.76/100,000 in 2006. No significant changes overtime in administrative districts were found. CONCLUSION: ALS mortality rates in São Paulo were lower in comparison to other countries, however any risk factor in our environment, lifestyle or genetic characteristics were found.

  15. Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.

    Science.gov (United States)

    Scekic-Zahirovic, Jelena; Oussini, Hajer El; Mersmann, Sina; Drenner, Kevin; Wagner, Marina; Sun, Ying; Allmeroth, Kira; Dieterlé, Stéphane; Sinniger, Jérôme; Dirrig-Grosch, Sylvie; René, Frédérique; Dormann, Dorothee; Haass, Christian; Ludolph, Albert C; Lagier-Tourenne, Clotilde; Storkebaum, Erik; Dupuis, Luc

    2017-06-01

    Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease.

  16. Impact of patient suffering on caregiver well-being: the case of amyotrophic lateral sclerosis patients and their caregivers.

    Science.gov (United States)

    Boerner, Kathrin; Mock, Steven E

    2012-01-01

    The impact of patient suffering on family caregivers is an understudied but important topic. This study of patients with amyotrophic lateral sclerosis (ALS) and their caregivers examined the associations of two components of patient suffering: patient physical symptoms, and mental distress, as well as the patient's support for the caregiver, with caregiver well-being. The sample consisted of 52 patients with ALS and their caregivers. Patients and caregivers each completed a structured survey assessing multiple domains including demographics, health, and well-being. Specifically, patients rated their own physical symptoms and mental distress. Caregivers rated their own daily affect, and the extent to which they perceived the patient as supportive. Caregivers also reported whether or not they had found any benefit in dealing with the patient's illness. Regression analyses yielded significant associations of patient distress with caregiver negative affect; patient support was associated with greater caregiver positive affect, and patient symptoms and support were associated with greater likelihood of caregiver benefit finding. There was a significant two-way interaction of patient symptoms by support, namely, benefit finding was not only more likely with greater physical suffering and patient support, but it was also the case that caregivers who perceived the care recipient as unsupportive could only find benefit when this person experienced intense physical suffering. Support interventions for ALS patients and their caregivers should devote particular attention to how caregivers may be affected by witnessing their loved one's sufferings, as well as identify and address challenges in support exchanges between caregivers and patients.

  17. Caregivers of patients with amyotrophic lateral sclerosis: investigating quality of life, caregiver burden, service engagement, and patient survival.

    Science.gov (United States)

    Burke, Tom; Galvin, Miriam; Pinto-Grau, Marta; Lonergan, Katie; Madden, Caoifa; Mays, Iain; Carney, Sile; Hardiman, Orla; Pender, Niall

    2017-05-01

    Few studies in amyotrophic lateral sclerosis (ALS) have profiled disease-specific features of the condition in conjunction with assessment of caregivers' burden, distress, quality of life, and investigated patient survival. Eighty-four ALS patients and their primary caregivers were enrolled. Patients completed ALS-specific measures of physical and cognitive function, while caregivers completed measures of anxiety, depression, caregiver burden, and quality of life. Patient-caregiver dyads were interviewed about their health-service utilisation. Survival data were obtained through the Irish register for ALS. Participants were dichotomised into low/high groups according to the severity of self-reported caregiver burden, based on statistically derived cut-off scores. High-burdened caregivers (n = 43) did not significantly differ from low-burdened caregivers (n = 41) with respect to disease-specific characteristics, i.e., ALSFRS-R, bulbar- or spinal-onset ALS, disease duration, or survival data. However, significant differences were reported on subjective measures of anxiety (p caregiver burden in ALS, and identify the importance of the psychological composition of caregivers. This study suggests that the subjective experience of individual caregivers is an important factor influencing the severity of experienced caregiver burden.

  18. Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice.

    Directory of Open Access Journals (Sweden)

    Young-Eun Yoo

    Full Text Available Amyotrophic lateral sclerosis (ALS is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT, which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients.

  19. Dysarthria and dysphagia in Amyotrophic Lateral Sclerosis with spinal onset: a study of quality of life related to swallowing.

    Science.gov (United States)

    da Costa Franceschini, Andressa; Mourão, Lucia Figueiredo

    2015-01-01

    Dysarthria and dysphagia are the most common clinical problems encountered in Amyotrophic Lateral Sclerosis and may reduce the quality of life. Evaluate the association of dysarthria and dysphagia and to evaluate the impact of dysphagia on swallowing quality of life in patients with ALS with spinal onset. Seventeen patients underwent to speech and swallowing evaluation and filled out self-report assessment of the Swallowing Quality of Life (SWAL-QOL). The dysarthria severity was graded using the Speech Subscale of ALS Severity Scale. The dysphagia severity was graded using a scale proposed by Dziweas et al., and the Functional Oral Intake Scale. Over 70% of the ALS patients with spinal onset had dysarthria and dysphagia. The correlation of dysarthria and dysphagia scales was statistically significant (p dysphagia severity and SWAL-QOL outcomes was significant for the same domains: "symptom frequency", "communication" and "fear of eating". The SWAL-QOL domains presented a mild to moderate impact on quality of life. Disease duration did not impact on SWAL-QOL. Dysarthria and dysphagia were common symptoms in patients with spinal onset of ALS and the swallowing quality of life decrease was directly related to with severity of dysarthria and dysphagia.

  20. Prognostic models based on patient snapshots and time windows: Predicting disease progression to assisted ventilation in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Carreiro, André V; Amaral, Pedro M T; Pinto, Susana; Tomás, Pedro; de Carvalho, Mamede; Madeira, Sara C

    2015-12-01

    Amyotrophic Lateral Sclerosis (ALS) is a devastating disease and the most common neurodegenerative disorder of young adults. ALS patients present a rapidly progressive motor weakness. This usually leads to death in a few years by respiratory failure. The correct prediction of respiratory insufficiency is thus key for patient management. In this context, we propose an innovative approach for prognostic prediction based on patient snapshots and time windows. We first cluster temporally-related tests to obtain snapshots of the patient's condition at a given time (patient snapshots). Then we use the snapshots to predict the probability of an ALS patient to require assisted ventilation after k days from the time of clinical evaluation (time window). This probability is based on the patient's current condition, evaluated using clinical features, including functional impairment assessments and a complete set of respiratory tests. The prognostic models include three temporal windows allowing to perform short, medium and long term prognosis regarding progression to assisted ventilation. Experimental results show an area under the receiver operating characteristics curve (AUC) in the test set of approximately 79% for time windows of 90, 180 and 365 days. Creating patient snapshots using hierarchical clustering with constraints outperforms the state of the art, and the proposed prognostic model becomes the first non population-based approach for prognostic prediction in ALS. The results are promising and should enhance the current clinical practice, largely supported by non-standardized tests and clinicians' experience. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Proteomic analysis of muscle affected by motor neuron degeneration: the wobbler mouse model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Staunton, Lisa; Jockusch, Harald; Ohlendieck, Kay

    2011-03-25

    Amyotrophic lateral sclerosis is the most common form of motor neuron disease in adult patients and characterized by progressive paralysis. The wobbler mouse (phenotype WR, genotype wr/wr) is an established animal model of human motor neuron disease and is characterized by a large variety of cellular abnormalities including muscular atrophy. In analogy to recent proteomic studies of cerebrospinal fluid and spinal cord, we have used here fluorescence difference in-gel electrophoresis to analyze global changes in the skeletal muscle proteome from WR versus normal mice. Relative concentrations of 21 proteins were found to be increased and 3 proteins were decreased. Mass spectrometric analysis identified these proteins to be associated with key metabolic pathways, the contractile apparatus, intermediate filaments and the cellular stress response. Drastically increased levels of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase were confirmed by immunoblotting and this finding agrees with the idea of an oxidative-to-glycolytic shift in disease-related muscular atrophy. The establishment of novel disease-specific biomarkers of motor neuron disease might be helpful in the design of improved diagnostic tools and the identification of novel therapeutic targets. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. A Neurodegeneration-Specific Gene-Expression Signature of Acutely Isolated Microglia from an Amyotrophic Lateral Sclerosis Mouse Model

    Directory of Open Access Journals (Sweden)

    Isaac M. Chiu

    2013-07-01

    Full Text Available Microglia are resident immune cells of the CNS that are activated by infection, neuronal injury, and inflammation. Here, we utilize flow cytometry and deep RNA sequencing of acutely isolated spinal cord microglia to define their activation in vivo. Analysis of resting microglia identified 29 genes that distinguish microglia from other CNS cells and peripheral macrophages/monocytes. We then analyzed molecular changes in microglia during neurodegenerative disease activation using the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS. We found that SOD1G93A microglia are not derived from infiltrating monocytes, and that both potentially neuroprotective and toxic factors, including Alzheimer’s disease genes, are concurrently upregulated. Mutant microglia differed from SOD1WT, lipopolysaccharide-activated microglia, and M1/M2 macrophages, defining an ALS-specific phenotype. Concurrent messenger RNA/fluorescence-activated cell sorting analysis revealed posttranscriptional regulation of microglia surface receptors and T cell-associated changes in the transcriptome. These results provide insights into microglia biology and establish a resource for future studies of neuroinflammation.

  3. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models.

    Science.gov (United States)

    Kim, Hyung-Jun; Raphael, Alya R; LaDow, Eva S; McGurk, Leeanne; Weber, Ross A; Trojanowski, John Q; Lee, Virginia M-Y; Finkbeiner, Steven; Gitler, Aaron D; Bonini, Nancy M

    2014-02-01

    Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily affecting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules. Unexpectedly, we found that genes that modulate stress granules are strong modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and Drosophila melanogaster. eIF2α phosphorylation is upregulated by TDP-43 toxicity in flies, and TDP-43 interacts with a central stress granule component, polyA-binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates abnormally, suggesting that prolonged stress granule dysfunction may contribute to pathogenesis. We investigated the efficacy of a small molecule inhibitor of eIF2α phosphorylation in ALS models. Treatment with this inhibitor mitigated TDP-43 toxicity in flies and mammalian neurons. These findings indicate that the dysfunction induced by prolonged stress granule formation might contribute directly to ALS and that compounds that mitigate this process may represent a novel therapeutic approach.

  4. Therapeutic modulation of eIF2α-phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models

    Science.gov (United States)

    Kim, Hyung-Jun; Raphael, Alya R.; LaDow, Eva S.; McGurk, Leeanne; Weber, Ross; Trojanowski, John Q.; Lee, Virginia M.-Y.; Finkbeiner, Steven; Gitler, Aaron D.; Bonini, Nancy M.

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily impacting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and Ataxin-2, is that they localize to stress granules. Unexpectedly, we found that genes that modulate stress granules are striking modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and Drosophila melanogaster, eIF2α phosphorylation is upregulated by TDP-43 toxicity in flies, and TDP-43 interacts with a central stress granule component polyA binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates abnormally, suggesting that prolonged stress granule dysfunction may contribute to pathogenesis. We investigated the efficacy of a small molecule inhibitor of eIF2α-phosphorylation in ALS models. This treatment mitigated TDP-43 toxicity in flies and mammalian neurons. These findings indicate that dysfunction induced by prolonged stress granule formation may contribute directly to ALS and that compounds that mitigate this process may represent a novel therapeutic approach. PMID:24336168

  5. Amyotrophic lateral sclerosis as a protein level, non-genomic disease: Therapy with S2RM exosome released molecules.

    Science.gov (United States)

    Maguire, Greg

    2017-11-26

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that leads to death. No effective treatments are currently available. Based on data from epidemiological, etiological, laboratory, and clinical studies, I offer a new way of thinking about ALS and its treatment. This paper describes a host of extrinsic factors, including the exposome, that disrupt the extracellular matrix and protein function such that a spreading, prion-like disease leads to neurodegeneration in the motor tracts. A treatment regimen is described using the stem cell released molecules from a number of types of adult stem cells to provide tissue dependent molecules that restore homeostasis, including proteostasis, in the ALS patient. Because stem cells themselves as a therapeutic are cumbersome and expensive, and when implanted in a host cause aging of the host tissue and often fail to engraft or remain viable, only the S2RM molecules are used. Rebuilding of the extracellular matrix and repair of the dysfunctional proteins in the ALS patient ensues.

  6. Epidemiological survey of amyotrophic lateral sclerosis in the province of Reggio Emilia, Italy: influence of environmental exposure to lead.

    Science.gov (United States)

    Guidetti, D; Bondavalli, M; Sabadini, R; Marcello, N; Vinceti, M; Cavalletti, S; Marbini, A; Gemignani, F; Colombo, A; Ferrari, A; Vivoli, G; Solimè, F

    1996-01-01

    We carried out a retrospective incidence, prevalence and mortality survey of amyotrophic lateral sclerosis (ALS) in the province of Reggio Emilia, northern Italy. Based on 79 patients, the mean incidence per year for the period 1980 through 1992 was 1.5 cases per 100,000. On December 31st, 1992, the prevalence rate was 5.4 per 100,000. In the 10-year period of 1983-1992 the average mortality rate was 1.3 per 100,000 per year. The average age at onset was 61.3 +/- 10.2, the average survival period thereafter was 26.3 months +/- 17.7; 27.3 +/- 17.6 for classic ALS, 19.5 +/- 8.4 for progressive bulbar palsy and 36.3 +/- 41.4 for pseudopolyneuritic ALS. The incidence rate, recorded in public health district No.12, an area with documented lead pollution since the 1970s, was standardized to the sex and age of the population of the province. Its incidence and prevalence rate were comparable to the rates found in the remaining area of the province.

  7. Establishment of In Vitro FUS-Associated Familial Amyotrophic Lateral Sclerosis Model Using Human Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Naoki Ichiyanagi

    2016-04-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms are yet to be elucidated due to limitations in the currently available human genetic data. In this study, we generated induced pluripotent stem cells (iPSC from two familial ALS (FALS patients with a missense mutation in the fused-in sarcoma (FUS gene carrying the heterozygous FUS H517D mutation, and isogenic iPSCs with the homozygous FUS H517D mutation by genome editing technology. These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability. Moreover, exon array analysis using motor neuron precursor cells (MPCs combined with CLIP-seq datasets revealed aberrant gene expression and/or splicing pattern in FALS MPCs. These results suggest that iPSC-derived motor neurons are a useful tool for analyzing the pathogenesis of human motor neuron disorders.

  8. Development of an electrooculogram-based eye-computer interface for communication of individuals with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Chang, Won-Du; Cha, Ho-Seung; Kim, Do Yeon; Kim, Seung Hyun; Im, Chang-Hwan

    2017-09-08

    Electrooculogram (EOG) can be used to continuously track eye movements and can thus be considered as an alternative to conventional camera-based eye trackers. Although many EOG-based eye tracking systems have been studied with the ultimate goal of providing a new way of communication for individuals with amyotrophic lateral sclerosis (ALS), most of them were tested with healthy people only. In this paper, we investigated the feasibility of EOG-based eye-writing as a new mode of communication for individuals with ALS. We developed an EOG-based eye-writing system and tested this system with 18 healthy participants and three participants with ALS. We also applied a new method for removing crosstalk between horizontal and vertical EOG components. All study participants were asked to eye-write specially designed patterns of 10 Arabic numbers three times after a short practice session. Our system achieved a mean recognition rates of 95.93% for healthy participants and showed recognition rates of 95.00%, 66.67%, and 93.33% for the three participants with ALS. The low recognition rates in one of the participants with ALS was mainly due to miswritten letters, the number of which decreased as the experiment proceeded. Our proposed eye-writing system is a feasible human-computer interface (HCI) tool for enabling practical communication of individuals with ALS.

  9. Use of a Human Artificial Chromosome for Delivering Trophic Factors in a Rodent Model of Amyotrophic Lateral Sclerosis

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    Yasuhiro Watanabe

    2015-01-01

    Full Text Available A human artificial chromosome (HAC is maintained as an episome within a cell and avoids random integration into the host genome. It can transfer multiple and/or large transgenes along with their regulatory elements thereby resembling native chromosomes. Using this HAC system, we established mesenchymal stem cells (MSCs that simultaneously expressed hepatocyte growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor 1, termed HAC-MSCs. This cell line provides an opportunity for stable transplantation and thorough analyses. We then introduced the cells for the treatment of a neurodegenerative disorder, amyotrophic lateral sclerosis. The HAC-MSCs were transplanted via the fourth cerebral ventricle (CV or intravenous (i.v. infusion at various ages of recipient mice. Littermate- and sex-matched mice underwent a sham procedure. Compared to the controls, there was an encouraging trend of increased life span via CV transplantation and delayed onset in i.v. infusion 60 days after transplantation. Further, we confirmed a statistically significant increase in life span via CV transplantation at 100 days. This effect was not seen in mice transplanted with MSCs lacking the HAC. We successfully enhanced the trophic potential of the MSCs using the HAC. This strategy could be a promising direction for the treatment of neurodegenerative disorders.

  10. Theoretical prediction of familial amyotrophic lateral sclerosis missense mutation effects on Cu/Zn superoxide dismutase structural stability

    Energy Technology Data Exchange (ETDEWEB)

    Potier, M.; Tu, Y. [Universite de Montreal, Quebec (Canada)

    1994-09-01

    Cu/Zn superoxide dismutase (SOD) deficiency is associated with the progressive paralytic disorder familial amyotrophic lateral sclerosis (FALS). Fifteen missense mutations in the SOD gene were identified in several patients. These mutations may prevent correct promoter folding or hamper homodimer formation necessary for SOD activity. To understand the effect of the missense mutations on SOD structure and function, we used a theoretical analysis of structural effects based on two predictive methods using the modeled tertiary structure of human SOD. The first method uses the TORSO program which optimizes amino acid side-chains repacking in both wild-type and mutant SODs and calculates protein internal packing energy. The second method uses a hydrophobicity scale of the amino acid residues and considers both solvent accessibility and hydrophobic nature of residue substitutions to compute a stabilization energy change ({delta}E). These predictive methods have been tested in 187 single and multiple missense mutants of 8 proteins (T4 lysozyme, human carbonic anhydrase II, chymotrypsin inhibitor 2, f1 gene V protein, barnase, {lambda}-repressor, chicken and human lysozymes) with experimentally determined thermostability. The overall prediction accuracy with these proteins was 88%. Analysis of FALS missense mutations {delta}E predicts that 14 of 15 mutations destabilize the SOD structure. The other missense mutation is located at the homodimer interface and may hinder dimer formation. This approach is applicable to any protein with known tertiary structure to predict missense mutation effects on protein stability.

  11. Pu-Erh Tea Extract Induces the Degradation of FET Family Proteins Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Yang Yu

    2014-01-01

    Full Text