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Sample records for amyotrophic lateral sclerosis the

  1. 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.

  2. 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.

  3. Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Vercruysse, Pauline; Sinniger, Jérôme; El Oussini, Hajer; Scekic-Zahirovic, Jelena; Dieterlé, Stéphane; Dengler, Reinhard; Meyer, Thomas; Zierz, Stephan; Kassubek, Jan; Fischer, Wilhelm; Dreyhaupt, Jens; Grehl, Torsten; Hermann, Andreas; Grosskreutz, Julian; Witting, Anke; Van Den Bosch, Ludo; Spreux-Varoquaux, Odile; Ludolph, Albert C; Dupuis, Luc

    2016-04-01

    Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic

  4. The cortical signature of amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Federica Agosta

    Full Text Available The aim of this study was to explore the pattern of regional cortical thickness in patients with non-familial amyotrophic lateral sclerosis (ALS and to investigate whether cortical thinning is associated with disease progression rate. Cortical thickness analysis was performed in 44 ALS patients and 26 healthy controls. Group differences in cortical thickness and the age-by-group effects were assessed using vertex-by-vertex and multivariate linear models. The discriminatory ability of MRI variables in distinguishing patients from controls was estimated using the Concordance Statistics (C-statistic within logistic regression analyses. Correlations between cortical thickness measures and disease progression rate were tested using the Pearson coefficient. Relative to controls, ALS patients showed a bilateral cortical thinning of the primary motor, prefrontal and ventral frontal cortices, cingulate gyrus, insula, superior and inferior temporal and parietal regions, and medial and lateral occipital areas. There was a significant age-by-group effect in the sensorimotor cortices bilaterally, suggesting a stronger association between age and cortical thinning in ALS patients compared to controls. The mean cortical thickness of the sensorimotor cortices distinguished patients with ALS from controls (C-statistic ≥ 0.74. Cortical thinning of the left sensorimotor cortices was related to a faster clinical progression (r = -0.33, p = 0.03. Cortical thickness measurements allowed the detection and quantification of motor and extramotor involvement in patients with ALS. Cortical thinning of the precentral gyrus might offer a marker of upper motor neuron involvement and disease progression.

  5. The cortical signature of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Agosta, Federica; Valsasina, Paola; Riva, Nilo; Copetti, Massimiliano; Messina, Maria Josè; Prelle, Alessandro; Comi, Giancarlo; Filippi, Massimo

    2012-01-01

    The aim of this study was to explore the pattern of regional cortical thickness in patients with non-familial amyotrophic lateral sclerosis (ALS) and to investigate whether cortical thinning is associated with disease progression rate. Cortical thickness analysis was performed in 44 ALS patients and 26 healthy controls. Group differences in cortical thickness and the age-by-group effects were assessed using vertex-by-vertex and multivariate linear models. The discriminatory ability of MRI variables in distinguishing patients from controls was estimated using the Concordance Statistics (C-statistic) within logistic regression analyses. Correlations between cortical thickness measures and disease progression rate were tested using the Pearson coefficient. Relative to controls, ALS patients showed a bilateral cortical thinning of the primary motor, prefrontal and ventral frontal cortices, cingulate gyrus, insula, superior and inferior temporal and parietal regions, and medial and lateral occipital areas. There was a significant age-by-group effect in the sensorimotor cortices bilaterally, suggesting a stronger association between age and cortical thinning in ALS patients compared to controls. The mean cortical thickness of the sensorimotor cortices distinguished patients with ALS from controls (C-statistic ≥ 0.74). Cortical thinning of the left sensorimotor cortices was related to a faster clinical progression (r = -0.33, p = 0.03). Cortical thickness measurements allowed the detection and quantification of motor and extramotor involvement in patients with ALS. Cortical thinning of the precentral gyrus might offer a marker of upper motor neuron involvement and disease progression.

  6. Amyotrophic lateral sclerosis mimic syndromes.

    Science.gov (United States)

    Ghasemi, Majid

    2016-04-03

    Amyotrophic lateral sclerosis (ALS) misdiagnosis has many broad implications for the patient and the neurologist. Potentially curative treatments exist for certain ALS mimic syndromes, but delay in starting these therapies may have an unfavorable effect on outcome. Hence, it is important to exclude similar conditions. In this review, we discuss some of the important mimics of ALS.

  7. 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…

  8. 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

  9. 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.

  10. Clinical Neurogenetics: Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Harms, Matthew B.; Baloh, Robert H.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, about which our understanding 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 for target for therapeutic development. This article reviews our current understanding of the heritability of ALS, 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. PMID:24176417

  11. Outcomes research in amyotrophic lateral sclerosis: lessons learned from the amyotrophic lateral sclerosis clinical assessment, research, and education database.

    Science.gov (United States)

    Miller, Robert G; Anderson, Fred; Brooks, Benjamin Rix; Mitsumoto, Hiroshi; Bradley, Walter G; Ringel, Steven P

    2009-01-01

    To examine the care of patients with ALS following the publication of the standardized recommendations for the management of patients with amyotrophic lateral sclerosis (ALS) published in 1999 by the American Academy of Neurology. Specific aspects of ALS patient management have been evaluated serially using a national Amyotrophic Lateral Sclerosis Clinical Assessment, Research, and Education (ALS CARE) database to encourage compliance with these recommendations and to assure continuing quality improvement. The most recent analysis of 5,600 patients shows interesting epidemiological observations and treatment trends. Proper management of many ALS symptoms has increased substantially since the first publication of the guidelines, and awareness of pseudobulbar affect has increased. Other recommendations are underutilized: Only 9% undergo percutaneous endoscopic gastrostomy, although this procedure was recommended in 22% of patients; and noninvasive positive pressure ventilation was used by only 21% of patients despite being associated with improved 5-year survival rates. This observational database has been a useful tool in monitoring compliance with the standard of care for patients with ALS and may have resulted in greater adherence to guidelines.

  12. Amyotrophic lateral sclerosis or not: Keys for the diagnosis.

    Science.gov (United States)

    Lenglet, T; Camdessanché, J-P

    2017-05-01

    Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease (MND) which prognosis is poor. Early diagnosis permit to set up immediately adapted treatment and cares. Available diagnostic criteria are based on the detection of both central and peripheral motor neuron injury in bulbar, cervical, thoracic and lumbar regions. Electrodiagnostic (EDX) tests are the key tools to identify peripheral motor neuron involvement. Needle examination records abnormal activities at rest, and looks for neurogenic pattern during muscle contraction. Motor unit potentials morphology is modified primary to recruitment. Motor evoked potentials remain the test of choice to identify impairment of central motor neurons. In the absence of diagnostic biomarker of ALS and among essential investigations of suspected MND, a careful clinical and neurophysiological work-up is essential to rule out the differential diagnosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  13. Amyotrophic lateral sclerosis and the clinical potential of dexpramipexole

    Directory of Open Access Journals (Sweden)

    Corcia P

    2012-08-01

    Full Text Available Philippe Corcia,1 Paul H Gordon21Centre SLA, CHRU de Tours, Tours, France; UMR INSERM U930, Université François Rabelais de Tours (PC, Tours, France; 2AP-HP, Hôpital de la Pitié-Salpêtrière, Département des Maladies du Système Nerveux (PHG, Paris, FranceAbstract: Amyotrophic lateral sclerosis (ALS is a neurodegenerative disorder that leads to progressive weakness from loss of motor neurons and death on average in less than 3 years after symptom onset. No clear causes have been found and just one medication, riluzole, extends survival. Researchers have identified some of the cellular processes that occur after disease onset, including mitochondrial dysfunction, protein aggregation, oxidative stress, excitotoxicity, inflammation, and apoptosis. Mitochondrial disease may be a primary event in neurodegeneration or occur secondary to other cellular processes, and may itself contribute to oxidative stress, excitotoxicity, and apoptosis. Clinical trials currently aim to slow disease progression by testing drugs that impact one or more of these pathways. While every agent tested in the 18 years after the approval of riluzole has been ineffective, basic and clinical research methods in ALS have become dramatically more sophisticated. Dexpramipexole (RPPX, the R(+ enantiomer of pramiprexole, which is approved for symptomatic treatment of Parkinson disease, carries perhaps the currently largest body of pre- and early clinical data that support testing in ALS. The neuroprotective properties of RPPX in various models of neurodegeneration, including the ALS murine model, may be produced through protective actions on mitochondria. Early phase trials in human ALS suggest that the drug can be taken safely by patients in doses that provide neuroprotection in preclinical models. A Phase III trial to test the efficacy of RPPX in ALS is underway.Keywords: dexpramipexole, amyotrophic lateral sclerosis, survival, clinical trials, neurodegeneration

  14. ALS (Amyotrophic Lateral Sclerosis)

    Science.gov (United States)

    ... FDA) has approved the drugs riluzole (Rilutek) and edaravone (Radicava) to treat ALS. Riluzole is believed to ... reverse the damage already done to motor neurons. Edaravone has been shown to slow the decline in ...

  15. Amyotrophic Lateral Sclerosis (ALS)

    Science.gov (United States)

    ... found for ALS. However, the drugs riluzole and edaravone have approved by the Food and Drug Administration ( ... 2-3 months but does not relieve symptoms. Edaravone can slow the clinical decline in daily functioning ...

  16. Amyotrophic lateral sclerosis (ALS)

    Science.gov (United States)

    Lou Gehrig disease; ALS; Upper and lower motor neuron disease; Motor neuron disease ... One out of 10 cases of ALS is due to a genetic defect. The cause is unknown in most other cases. In ALS, motor nerve cells (neurons) waste away ...

  17. Traces of disease in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Verstraete, E.

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive disease of the motor system involving both upper motor neurons in the brain and lower motor neurons in the spinal cord. Patients suffer from progressive wasting and weakness of limb, bulbar and respiratory muscles. Onset and disease course in ALS

  18. 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.

  19. Racing against the clock: recognizing, differentiating, diagnosing, and referring the amyotrophic lateral sclerosis patient.

    Science.gov (United States)

    Shook, Steven J; Pioro, Erik P

    2009-01-01

    Recognition of the early symptoms and signs in amyotrophic lateral sclerosis, exclusion of alternative diagnoses, and referral to a tertiary center can have a significant positive impact on the lives of patients and their caregivers. This article provides the most current amyotrophic lateral sclerosis criteria, as well as helpful clinical clues to the diagnosis. An approach to laboratory testing, electrodiagnostic testing, and imaging to exclude diseases that mimic ALS also are discussed, as are atypical presentations that can confound timely diagnosis.

  20. Subtle involvement of the sympathetic nervous system in amyotrophic lateral sclerosis.

    NARCIS (Netherlands)

    Oey, P.L.; Vos, P.E.; Wieneke, G.H.; Wokke, J.H.J.; Blankestijn, P.J.; Karemaker, J.M.

    2002-01-01

    The literature on the involvement of the autonomic nervous system (ANS) in amyotrophic lateral sclerosis (ALS) is conflicting. We therefore investigated several aspects of autonomic function, namely muscle sympathetic nerve activity (MSNA), blood pressure, cardiac function (electrocardiogram; ECG),

  1. Subtle involvement of the sympathetic nervous system in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Oey, P. Liam; Vos, Pieter E.; Wieneke, George H.; Wokke, John H. J.; Blankestijn, Peter J.; Karemaker, John M.

    2002-01-01

    The literature on the involvement of the autonomic nervous system (ANS) in amyotrophic lateral sclerosis (ALS) is conflicting. We therefore investigated several aspects of autonomic function, namely muscle sympathetic nerve activity (MSNA), blood pressure, cardiac function (electrocardiogram; ECG),

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

    KAUST Repository

    Conti, Antonio; Riva, Nilo; Pesca, Mariasabina Sabina; Iannaccone, Sandro; Cannistraci, Carlo; Corbo, Massimo; Previtali, Stefano Carlo; Quattrini, Angelo; Alessio, Massimo

    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

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

    Science.gov (United States)

    Shepheard, Stephanie R; Chataway, Tim; Schultz, David W; Rush, Robert A; Rogers, Mary-Louise

    2014-01-01

    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 (pneurotrophin 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.

  4. 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.

  5. Ethical considerations in the management of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Eisen, Andrew; Krieger, Charles

    2013-11-01

    This article examines some of the ethical concerns relevant for the management of amyotrophic lateral sclerosis (ALS). We emphasize the importance for providing a competent assessment of the clinical deficit to correctly identify the disease and to avoid incorrect diagnoses. Conveying the diagnosis to the patient and their family requires empathy and it is important to remain supportive and positive, even in the face of this incurable disease. The essence of care in ALS is to permit the patient to have optimal function for their level of ability. This may require the use of gastrostomy and non-invasive or permanent ventilation. Employment of a multi-disciplinary team will permit optimization of patient care to achieve a good quality of life for as long as possible. The patient should also be informed of the risks associated with unproven therapies and the risks and potential benefits of therapeutic trials. The wishes of patients in regard to gastrostomy, long-term ventilation and end-of life decisions must be considered in an unbiased fashion. Recent advances in the genetics of familial ALS (FALS) have demonstrated some overlap between FALS, sporadic ALS and fronto-temporal lobar dementia (FTLD). The interpretation and dissemination of the results of genetic testing although important can induce confusion, considerable anxiety and guilt in patients and their families and proper counseling is imperative. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. The corticospinal tract in amyotrophic lateral sclerosis: an MRI study

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    Hofmann, E.; Warmuth-Metz, M. [Department of Neuroradiology, University of Wuerzburg (Germany); Ochs, G.; Pelzl, A. [Department of Neurology, University of Wuerzburg, Wuerzburg (Germany)

    1998-02-01

    Cortical motor neurone loss and corticospinal tract (CST) degeneration are typical of amyotrophic lateral sclerosis (ALS). It is a matter of debate whether qualitative assessment of the CST by MRI is useful in the diagnosis. It is also an open question whether quantitative determination of the T2 relaxation times can improve its value. Signal intensity along the CST on 14 consecutive slices was assessed using arbitrary visual rating on double-echo T2-weighted and proton-density spin-echo images of 21 patients with ALS and 21 age- and sex-matched controls. T2 was determined quantitatively. On the T2-weighted images the patients` ratings did not differ from that of controls. The T2 of patients and controls showed no statistical difference in any slice. There was no correlation between T2 and patient age, duration of the disease, or predominant bulbar, lower or upper motor neurone signs. The only correlation between MRI findings and disease was on the proton-density images: all cases in which the CST was poorly seen were controls; a clearly high-signal CST was seen only in the patients. High conspicuity of the CST was thus specific but not sensitive for the diagnosis of ALS. T2-weighted images and measurement of T2 were not useful for diagnosis. (orig.) With 2 figs., 1 tab., 26 refs.

  7. Factors affecting the diagnostic delay in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Cellura, Eleonora; Spataro, Rossella; Taiello, Alfonsa Claudia; La Bella, Vincenzo

    2012-07-01

    Although amyotrophic lateral sclerosis (ALS) is a relentlessly progressive disorder, early diagnosis allows a prompt start with the specific drug riluzole and an accurate palliative care planning. ALS at onset may however mimic several disorders, some of them treatable (e.g., multifocal motor neuropathy) or epidemiologically more frequent (e.g., cervical myelopathy). To study the delay from onset to diagnosis in a cohort of ALS patients and to the variables that may affect it. We performed a retrospective analysis of the diagnostic delays in a cohort of 260 patients affected by ALS (M/F = 1.32) followed at our tertiary referral ALS Center between 2000 and 2007. The median time from onset to diagnosis was 11 months (range: 6-21) for the whole ALS cohort, 10 months (range: 6-15) in bulbar-onset (n = 65) and 12 months (range: 7-23) in spinal-onset (n = 195) patients (p = 0.3). 31.1% of patients received other diagnoses before ALS and this led to a significant delay of the correct diagnosis in this group (other diagnoses before ALS, n = 81: median delay, 15 months [9.75-24.25] vs ALS, n = 179, median delay, 9 months [6-15.25], p heuristics might represent an important contributing factor. Furthermore, the length of the differential diagnosis from other disorders and delays in referral to the neurologist seems to be positively associated with the delay in diagnosis. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. The increasing importance of environmental conditions in amyotrophic lateral sclerosis

    Science.gov (United States)

    Riancho, Javier; Bosque-Varela, Pilar; Perez-Pereda, Sara; Povedano, Mónica; de Munaín, Adolfo López; Santurtun, Ana

    2018-04-01

    Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MNs). Although a small percentage of ALS has a familial origin, the vast majority of cases are sporadic in which genetic factors and environment interact with each other leading to disease onset in genetically predisposed individuals. In the current model of the disease, each individual has a determined genetic load, some degree of cell degeneration related to age and several risky environmental exposures. In this scenario, MN degeneration would occur when the sum of these factors reach a certain threshold. To date, an extensive list of environmental factors has been associated to ALS, including different categories, such as exposure to heavy metals and other toxicants, cyanotoxins or infectious agents. In addition, in recent years, lifestyle and other demographic parameters are gaining relevance in the genesis of the disease. Among them, physical activity, nutrition, body mass index, cardiovascular risk factors, autoimmune diseases and cancer are some of the conditions which have been related to the disease. In this review, we will discuss the potential mechanisms of environmental conditions in motor neuron degeneration. Understanding the role of each one of these factors as well as their interactions appears as a crucial step in order to develop new preventive, diagnostic and therapeutic approaches for ALS patients.

  9. 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.

  10. Workplace exposures and the risk of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Fang, Fang; Quinlan, Patricia; Ye, Weimin; Barber, Marie K; Umbach, David M; Sandler, Dale P; Kamel, Freya

    2009-09-01

    Occupation has been suggested to play a role in amyotrophic lateral sclerosis (ALS) etiology, but detailed information on the importance of specific workplace exposures is lacking. Our aim was to assess the relationship between workplace exposures and the risk of ALS and to evaluate potential interactions between these exposures and smoking. We conducted a case-control study in New England between 1993 and 1996, comprising 109 cases and 253 controls who completed a structured interview covering occupations and workplace exposures. Unconditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for ALS. Analyses were conducted among the entire study population and after stratification by smoking. We observed a higher risk of ALS for construction workers excluding supervisors (OR = 2.9; 95% CI, 1.2-7.2) and precision metal workers (OR = 3.5; 95% CI, 1.2-10.5). Self-reported exposures to paint strippers; cutting, cooling, or lubricating oils; antifreeze or coolants; mineral or white spirits; and dry cleaning agents each appeared to be associated with a 60-90% higher risk. Specific chemicals related to a > 50% increase in risk of ALS included aliphatic chlorinated hydrocarbons, glycols, glycol ethers, and hexane. Relative risks associated with these workplace exposures and chemicals were greater among nonsmokers and persisted in mutually adjusted models. Our data suggest that certain occupations and workplace exposures may be associated with increased risk of ALS. These results need to be confirmed in independent populations.

  11. Assessment of the upper motor neuron in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Huynh, William; Simon, Neil G; Grosskreutz, Julian; Turner, Martin R; Vucic, Steve; Kiernan, Matthew C

    2016-07-01

    Clinical signs of upper motor neuron (UMN) involvement are an important component in supporting the diagnosis of amyotrophic lateral sclerosis (ALS), but are often not easily appreciated in a limb that is concurrently affected by muscle wasting and lower motor neuron degeneration, particularly in the early symptomatic stages of ALS. Whilst recent criteria have been proposed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains essentially clinical. As a result, there is often a significant diagnostic delay that in turn may impact institution of disease-modifying therapy and access to other optimal patient management. Biomarkers of pathological UMN involvement are also required to ensure patients with suspected ALS have timely access to appropriate therapeutic trials. The present review provides an analysis of current and recently developed assessment techniques, including novel imaging and electrophysiological approaches used to study corticomotoneuronal pathology in ALS. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  12. High-Resolution 7T MR Imaging of the Motor Cortex in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Cosottini, M; Donatelli, G; Costagli, M; Caldarazzo Ienco, E; Frosini, D; Pesaresi, I; Biagi, L; Siciliano, G; Tosetti, M

    2016-03-01

    Amyotrophic lateral sclerosis is a progressive motor neuron disorder that involves degeneration of both upper and lower motor neurons. In patients with amyotrophic lateral sclerosis, pathologic studies and ex vivo high-resolution MR imaging at ultra-high field strength revealed the co-localization of iron and activated microglia distributed in the deep layers of the primary motor cortex. The aims of the study were to measure the cortical thickness and evaluate the distribution of iron-related signal changes in the primary motor cortex of patients with amyotrophic lateral sclerosis as possible in vivo biomarkers of upper motor neuron impairment. Twenty-two patients with definite amyotrophic lateral sclerosis and 14 healthy subjects underwent a high-resolution 2D multiecho gradient-recalled sequence targeted on the primary motor cortex by using a 7T scanner. Image analysis consisted of the visual evaluation and quantitative measurement of signal intensity and cortical thickness of the primary motor cortex in patients and controls. Qualitative and quantitative MR imaging parameters were correlated with electrophysiologic and laboratory data and with clinical scores. Ultra-high field MR imaging revealed atrophy and signal hypointensity in the deep layers of the primary motor cortex of patients with amyotrophic lateral sclerosis with a diagnostic accuracy of 71%. Signal hypointensity of the deep layers of the primary motor cortex correlated with upper motor neuron impairment (r = -0.47; P amyotrophic lateral sclerosis. Cortical thinning and signal hypointensity of the deep layers of the primary motor cortex could constitute a marker of upper motor neuron impairment in patients with amyotrophic lateral sclerosis. © 2016 by American Journal of Neuroradiology.

  13. 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.

  14. The Big Bluff of Amyotrophic Lateral Sclerosis Diagnosis: The Role of Neurodegenerative Disease Mimics.

    Science.gov (United States)

    Bicchi, Ilaria; Emiliani, Carla; Vescovi, Angelo; Martino, Sabata

    2015-01-01

    Neurodegenerative diseases include a significant number of pathologies affecting the nervous system. Generally, the primary cause of each disease is specific; however, recently, it was shown that they may be correlated at molecular level. This aspect, together with the exhibition of similar symptoms, renders the diagnosis of these disorders difficult. Amyotrophic lateral sclerosis is one of these pathologies. Herein, we report several cases of amyotrophic lateral sclerosis misdiagnosed as a consequence of features that are common to several neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's disease, spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia and frontotemporal dementia, and mostly with the lysosomal storage disorder GM2 gangliosidosis. Overall reports highlight that the differential diagnosis for amyotrophic lateral sclerosis should include correlated mechanisms. © 2015 S. Karger AG, Basel.

  15. 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.

  16. c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    2015-03-01

    1 AWARD NUMBER: W81XWH-12-1-0431 TITLE: “c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Sclerosis ” PRINCIPAL...TITLE AND SUBTITLE “c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Scelerosis” 5a. CONTRACT NUMBER 5b. GRANT NUMBER... Lateral   Sclerosis ”   Final  Report:  Project  Period  Sept  2012-­‐Dec  2014     Personnel  List:     Feng,  Yangbo

  17. Palliative care for patients in the USA with amyotrophic lateral sclerosis: current challenges

    Directory of Open Access Journals (Sweden)

    Houseman G

    2015-11-01

    Full Text Available Gail Houseman,1 Mary Kelley2 1The ALS Association Greater Philadelphia Chapter, Ambler, PA, USA; 2Department of Neurology, ALS Center at Penn Medicine, Philadelphia, PA, USA Abstract: Amyotrophic lateral sclerosis (ALS is a motor neuron disease that results in eventual paralysis of all voluntary muscles. Cognitive impairment may be a co-occurring condition with the ALS patient. Palliative care, which involves symptom management, is the most utilized treatment of choice. Managing the symptoms of ALS can be challenging. This paper provides experience-based facts on daily care provision in the USA and some practical guidelines. Keywords: amyotrophic lateral sclerosis, ALS, palliative care, challenges, symptom management

  18. MR imaging of amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Oba, Hiroshi; Monzawa, Shuichi (Yamanashi Medical College, Nakakoma (Japan). Hospital); Araki, Tsutomu (and others)

    1992-04-01

    Magnetic resonance imaging (MR imaging) provides a sensitive method for mapping the normal and pathological distribution of iron in the brain. High field strength MR imaging (1.5 T) was used to evaluate eight patients with amyotrophic lateral sclerosis (ALS) and 49 neurological normal control patients. All eight ALS patients showed decreased signal intensity in the motor cortex on T2-weighted images, while only one of the normal control patients showed this finding. The results suggested that the decreased signal intensity in the motor cortex in ALS was caused by the deposition of iron in this area. (author).

  19. [Local demyelination in amyotrophic lateral sclerosis].

    Science.gov (United States)

    Kvirkvelia, N; Shakarishvili, R

    2013-02-01

    It is well known that the demyelination of peripheral nerves can be diffuse or local. Pathogenesis of acute or chronic inflamentary demyelination polyneurophathy is based on diffuse demyelination. Local demyelination occured by conduction block with electoneuromyographic (ENMG) researches. It is the main characteristic of multifocal motor neuropathy (MMN). Generally it is considered, that conduction block is not usual for amyotrophic lateral sclerosis (ALS). More over, its existance excludes this diagnosis. The article discribes 3 cases of ALS with conduction block verified with ENMG researches. Article also deals with pathogenetic mechanisms of conduction block in ALS and MMN. In addition it observes the issues of differential diagnosis between ALS and MMW.

  20. 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...

  1. Genotyping of presenilin-1 polymorphism in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Panas, M; Karadima, G; Kalfakis, N; Psarrou, O; Floroskoufi, P; Kladi, A; Petersen, M B; Vassilopoulos, D

    2000-12-01

    The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis are not fully understood. Recent studies suggest that apoptosis is involved in the abnormal neural death that occurs in this devastating disease. Presenilin-1, a transmembrane protein, seems to be implicated in apoptosis. To determine whether presenilin-1 intron 8 polymorphism has an influence in the course of amyotrophic lateral sclerosis, we examined this polymorphism genotypes in a large group of patients (n = 72) with amyotrophic lateral sclerosis and in a random sample of 213 healthy individuals. The results showed a significant difference in genotype (P < 0.04) and allele (P < 0.03) distribution between patients controls. These results suggest a possible intervention of presenilin-1 in the pathogenesis of amyotrophic lateral sclerosis.

  2. 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,

  3. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis

    OpenAIRE

    Orlacchio, Antonio; Babalini, Carla; Borreca, Antonella; Patrono, Clarice; Massa, Roberto; Basaran, Sarenur; Munhoz, Renato P.; Rogaeva, Ekaterina A.; St George-Hyslop, Peter H.; Bernardi, Giorgio; Kawarai, Toshitaka

    2010-01-01

    The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Common clinical, pathological and genetic features between amyotrophic lateral sclerosis and hereditary spastic paraplegia motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene. The inclusion criterion was a diagnosis of clinically definite ...

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

    NARCIS (Netherlands)

    Tortarolo, Massimo; Lo Coco, Daniele; Veglianese, Pietro; Vallarola, Antonio; Giordana, Maria Teresa; Marcon, Gabriella; Beghi, Ettore; Poloni, Marco; Strong, Michael J.; Iyer, Anand M.; Aronica, Eleonora; Bendotti, Caterina

    2017-01-01

    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

  5. 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…

  6. 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.

  7. Neurofilament and glial alterations in the cerebral cortex in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Troost, D.; Sillevis Smitt, P. A.; de Jong, J. M.; Swaab, D. F.

    1992-01-01

    According to the literature, only minor nonspecific histopathological lesions are present in the motor cortex in up to 90% of the amyotrophic lateral sclerosis (ALS) patients. These observations, however, have so far been based mainly on conventional staining techniques. An exception to this is the

  8. 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.

  9. 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…

  10. [The differential diagnosis of amyotrophic lateral sclerosis and subacute herpes virus myelitis].

    Science.gov (United States)

    Levitsky, G N; Zavalishin, E E; Chub, R V; Morozova, E A; Serkov, S V

    2016-01-01

    Differential diagnosis of incurable and potentially curable neurological diseases is an urgent problem of modern neurology. The authors present a case report of subacute herpes virus myelitis, a rare complication of herpes infection by Varicella-Zoster virus. The differential diagnosis with amyotrophic lateral sclerosis is described.

  11. Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients

    OpenAIRE

    DeYoung Joseph; Langfelder Peter; Fuller Tova F; Blauw Hylke M; van Es Michael A; van Vught Paul WJ; Horvath Steve; Saris Christiaan GJ; Wokke John HJ; Veldink Jan H; van den Berg Leonard H; Ophoff Roel A

    2009-01-01

    Abstract Background Amyotrophic Lateral Sclerosis (ALS) is a lethal disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Diagnosis is mainly based on clinical symptoms, and there is currently no therapy to stop the disease or slow its progression. Since access to spinal cord tissue is not possible at disease onset, we investigated changes in...

  12. A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK.

    Science.gov (United States)

    Morgan, Sarah; Shatunov, Aleksey; Sproviero, William; Jones, Ashley R; Shoai, Maryam; Hughes, Deborah; Al Khleifat, Ahmad; Malaspina, Andrea; Morrison, Karen E; Shaw, Pamela J; Shaw, Christopher E; Sidle, Katie; Orrell, Richard W; Fratta, Pietro; Hardy, John; Pittman, Alan; Al-Chalabi, Ammar

    2017-06-01

    Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

  13. 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

  14. Elastin cross-linking in the skin from patients with amyotrophic lateral sclerosis

    Science.gov (United States)

    Ono, S.; Yamauchi, M.

    1994-01-01

    Two cross-links unique to elastin, desmosine and isodesmosine were measured and compared in skin tissue (left upper arm) from 10 patients with amyotrophic lateral sclerosis (ALS) and from seven age-matched controls. The contents of desmosine and isodesmosine were significantly decreased (p elastin is affected in ALS.

  15. The predictive value of respiratory function tests for non-invasive ventilation in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Tilanus, T.B.M.; Groothuis, J.T.; Broek-Pastoor, J.M.C. ten; Feuth, T.; Heijdra, Y.F.; Slenders, J.P.L.; Doorduin, J.; Engelen, B.G.M. van; Kampelmacher, M.J.; Raaphorst, J.

    2017-01-01

    BACKGROUND: Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. The timing of referral to a home ventilation service (HVS), which is in part based on respiratory function tests, has shown room for improvement. It is currently unknown

  16. The predictive value of respiratory function tests for non-invasive ventilation in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Tilanus, T. B. M.; Groothuis, J. T.; TenBroek-Pastoor, J. M. C.; Feuth, T. B.; Heijdra, Y. F.; Slenders, J. P. L.; Doorduin, J.; van Engelen, B. G.; Kampelmacher, M. J.; Raaphorst, J.

    2017-01-01

    Background: Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. The timing of referral to a home ventilation service (HVS), which is in part based on respiratory function tests, has shown room for improvement. It is currently unknown

  17. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis.

    Science.gov (United States)

    Orlacchio, Antonio; Babalini, Carla; Borreca, Antonella; Patrono, Clarice; Massa, Roberto; Basaran, Sarenur; Munhoz, Renato P; Rogaeva, Ekaterina A; St George-Hyslop, Peter H; Bernardi, Giorgio; Kawarai, Toshitaka

    2010-02-01

    The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Common clinical, pathological and genetic features between amyotrophic lateral sclerosis and hereditary spastic paraplegia motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene. The inclusion criterion was a diagnosis of clinically definite amyotrophic lateral sclerosis according to the revised El Escorial criteria. The exclusion criterion was a diagnosis of hereditary spastic paraplegia with thin corpus callosum in line with an established protocol. Additional pathological and genetic evaluations were also performed. Surprisingly, 12 sequence alterations in the spatacsin gene (one of which is novel, IVS30 + 1 G > A) were identified in 10 unrelated pedigrees with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival. The countries of origin of these families were Italy, Brazil, Canada, Japan and Turkey. The variants seemed to be pathogenic since they co-segregated with the disease in all pedigrees, were absent in controls and were associated with amyotrophic lateral sclerosis neuropathology in one member of one of these families for whom central nervous system tissue was available. Our study indicates that mutations in the spatascin gene could cause a much wider spectrum of clinical features than previously recognized, including autosomal recessive juvenile amyotrophic lateral sclerosis.

  18. 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

  19. 76 FR 78823 - Schedule for Rating Disabilities; Evaluation of Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    2011-12-20

    ...; Evaluation of Amyotrophic Lateral Sclerosis AGENCY: Department of Veterans Affairs. ACTION: Final rule... revising the disability evaluation criterion provided for amyotrophic lateral sclerosis (ALS) to provide an...) a proposed rule that would revise the evaluation criterion for amyotrophic lateral sclerosis (ALS...

  20. Spinal Cord Gray Matter Atrophy in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Paquin, M-Ê; El Mendili, M M; Gros, C; Dupont, S M; Cohen-Adad, J; Pradat, P-F

    2018-01-01

    There is an emerging need for biomarkers to better categorize clinical phenotypes and predict progression in amyotrophic lateral sclerosis. This study aimed to quantify cervical spinal gray matter atrophy in amyotrophic lateral sclerosis and investigate its association with clinical disability at baseline and after 1 year. Twenty-nine patients with amyotrophic lateral sclerosis and 22 healthy controls were scanned with 3T MR imaging. Standard functional scale was recorded at the time of MR imaging and after 1 year. MR imaging data were processed automatically to measure the spinal cord, gray matter, and white matter cross-sectional areas. A statistical analysis assessed the difference in cross-sectional areas between patients with amyotrophic lateral sclerosis and controls, correlations between spinal cord and gray matter atrophy to clinical disability at baseline and at 1 year, and prediction of clinical disability at 1 year. Gray matter atrophy was more sensitive to discriminate patients with amyotrophic lateral sclerosis from controls ( P = .004) compared with spinal cord atrophy ( P = .02). Gray matter and spinal cord cross-sectional areas showed good correlations with clinical scores at baseline ( R = 0.56 for gray matter and R = 0.55 for spinal cord; P amyotrophic lateral sclerosis. © 2018 by American Journal of Neuroradiology.

  1. 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... under this section: (1) If there is affirmative evidence that amyotrophic lateral sclerosis was not...

  2. 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.

  3. Amyotrophic lateral sclerosis: update and new developments

    Science.gov (United States)

    Pratt, Ashley J; Getzoff, Elizabeth D; Perry, J Jefferson P

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. It is typically characterized by adult-onset degeneration of the upper and lower motor neurons, and is usually fatal within a few years of onset. A subset of ALS patients has an inherited form of the disease, and a few of the known mutant genes identified in familial cases have also been found in sporadic forms of ALS. Precisely how the diverse ALS-linked gene products dictate the course of the disease, resulting in compromised voluntary muscular ability, is not entirely known. This review addresses the major advances that are being made in our understanding of the molecular mechanisms giving rise to the disease, which may eventually translate into new treatment options. PMID:23019386

  4. 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.

  5. 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...... cells working together are necessary for the pathogenesis of the disease. Observed immune system alterations could indicate an active participation in this mechanism. Damaged motor neurons are able to activate microglia, astrocytes and the complement system, which further can influence each other...... and contribute to neurodegeneration. Infiltrating peripheral immune cells appears to correlate with disease progression, but their significance and composition is unclear. The deleterious effects of this collaborating system of cells appear to outweigh the protective aspects, and revealing this interplay might...

  6. Irradiation of salivary glands in the amyotrophic lateral sclerosis; Irradiation des glandes salivaires dans la sclerose laterale amyotrophique

    Energy Technology Data Exchange (ETDEWEB)

    Bourry, N.; Lapeyre, M.; Tortochaux, J.; Gilliot, O.; Achard, J.L.; Verrelle, P. [Centre Jean-Perrin, Dept. de Radiotherapie 63 - Clermont-Ferrand (France); Clavelou, P.; Rouvet, S. [CHU Gabriel-Montpied, Service de Neurologie, 63 - Clermont-Ferrand (France)

    2006-11-15

    The irradiation of salivary glands in the amyotrophic lateral sclerosis is efficient. A dose about 20 Gy in five seances delivered by electrons seems a correct compromise between efficiency and toxicity. (N.C.)

  7. A comprehensive review of amyotrophic lateral sclerosis

    Science.gov (United States)

    Zarei, Sara; Carr, Karen; Reiley, Luz; Diaz, Kelvin; Guerra, Orleiquis; Altamirano, Pablo Fernandez; Pagani, Wilfredo; Lodin, Daud; Orozco, Gloria; Chinea, Angel

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5–10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease. PMID:26629397

  8. [Neurophysiological investigations in amyotrophic lateral sclerosis].

    Science.gov (United States)

    Camdessanché, Jean-Philippe; Lenglet, Timothée

    2014-05-01

    Amyotrophic lateral sclerosis (ALS) is a degenerative disease which prognosis is poor. Early diagnosis permits to set up immediately adapted treatment and cares. Available diagnostic criteria are based on the detection of both the central and peripheral motor neuron injury in bulbar, cervical, thoracic and lumbar regions. Electromyographic study is the key tool to identify peripheral motor neuron involvement. Conduction velocities are systematically performed to rule out differential diagnosis. Needle examination records abnormal activities at rest and looks for neurogenic pattern during muscle contraction. Motor unit potentials morphology is modified primary to recruitment. Motor evoked potentials remain the test of choice to identify impairment of central motor neurons. For the monitoring of ALS patients, the MUNE technique (motor unit number estimation) seems the most interesting. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. MR imaging appearance of amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Carvlin, M.J.; Fielding, R.; Rajan, S.S.; Muraki, A.; Manz, G.; Schellinger, D.; Hackney, D.B.

    1989-01-01

    The authors have investigated fresh (normal) and fixed (histologically proven amyotrophic lateral sclerosis [ALS]) cord specimens using high-resolution MR techniques in order to document, accurately and noninvasively, the internal structure of the spinal cord. Short TR/TE (500/27 [repetition time/echo time, msec]) and long TR/TE (2,00/54) spin-echo images were obtained in the axial, sagittal, and coronal planes at 4.7 T (Varian), with inplane resolution of either 85 x 150 or 40 x 50 μm, section thickness of 0.8-1.5 mm. In the ALS cords, the bilateral degeneration of corticospinal tracts was well visualized as areas of high signal intensity on both short TR/TE and long TR/TE images

  10. Therapeutic neuroprotective agents for amyotrophic lateral sclerosis

    Science.gov (United States)

    Pandya, Rachna S.; Zhu, Haining; Li, Wei; Bowser, Robert; Friedlander, Robert M.

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal chronic neurodegenerative disease whose hallmark is proteinaceous, ubiquitinated, cytoplasmic inclusions in motor neurons and surrounding cells. Multiple mechanisms proposed as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. It is therefore essential to gain a better understanding of the underlying disease etiology and search for neuroprotective agents that might delay disease onset, slow progression, prolong survival, and ultimately reduce the burden of disease. Because riluzole, the only Food and Drug Administration (FDA)-approved treatment, prolongs the ALS patient’s life by only 3 months, new therapeutic agents are urgently needed. In this review, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression. PMID:23864030

  11. Implementation of a population-based epidemiological rare disease registry: study protocol of the amyotrophic lateral sclerosis (ALS) - registry Swabia

    OpenAIRE

    Nagel, Gabriele; ?nal, Hatice; Rosenbohm, Angela; Ludolph, Albert C; Rothenbacher, Dietrich

    2013-01-01

    Abstract Background The social and medical impact of rare diseases is increasingly recognized. Amyotrophic lateral sclerosis (ALS) is the most prevalent of the motor neuron diseases. It is characterized by rapidly progressive damage to the motor neurons with a survival of 2–5 years for the majority of patients. The objective of this work is to describe the study protocol and the implementation steps of the amyotrophic lateral sclerosis (ALS) registry Swabia, located in the South of Germany. M...

  12. 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.

  13. Reduced isotope uptake restricted to the motor area in patients with amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Abe, K.; Yorifuji, S.; Nishikawa, Y.

    1993-01-01

    To study degeneration in the central nervous system in amyotrophic lateral sclerosis (ALS), we studied four patients using single photon emission tomography (SPECT) and magnetic resonance imaging (MRI). MRI demonstrated high intensity along the pyramidal tract on T2-weighted images in two. SPECT demonstrated reduced isotope uptake restricted to the motor area. While the cause of degeneration of the cortical neurons in the motor area is unknown, SPECT is useful for detecting the degeneration in patients with ALS. (orig.)

  14. Amyotrophic lateral sclerosis (ALS): three letters that change the people's life. For ever

    OpenAIRE

    Oliveira,Acary Souza Bulle; Pereira,Roberto Dias Batista

    2009-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. Currently, we rely on a mu...

  15. The ratio of N-acetyl aspartate to glutamate correlates with disease duration of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Sako, Wataru; Abe, Takashi; Izumi, Yuishin; Harada, Masafumi; Kaji, Ryuji

    2016-05-01

    Glutamate (Glu)-induced excitotoxicity has been implicated in the neuronal loss of amyotrophic lateral sclerosis. To test the hypothesis that Glu in the primary motor cortex contributes to disease severity and/or duration, the Glu level was investigated using MR spectroscopy. Seventeen patients with amyotrophic lateral sclerosis were diagnosed according to the El Escorial criteria for suspected, possible, probable or definite amyotrophic lateral sclerosis, and enrolled in this cross-sectional study. We measured metabolite concentrations, including N-acetyl aspartate (NAA), creatine, choline, inositol, Glu and glutamine, and performed partial correlation between each metabolite concentration or NAA/Glu ratio and disease severity or duration using age as a covariate. Considering our hypothesis that Glu is associated with neuronal cell death in amyotrophic lateral sclerosis, we investigated the ratio of NAA to Glu, and found a significant correlation between NAA/Glu and disease duration (r=-0.574, p=0.02). The "suspected" amyotrophic lateral sclerosis patients showed the same tendency as possible, probable and definite amyotrophic lateral sclerosis patients in regard to correlation of NAA/Glu ratio with disease duration. The other metabolites showed no significant correlation. Our findings suggested that glutamatergic neurons are less vulnerable compared to other neurons and this may be because inhibitory receptors are mainly located presynaptically, which supports the notion of Glu-induced excitotoxicity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Use of Sugammadex in a Patient with Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Kelsaka, Ebru; Karakaya, Deniz; Zengin, Eyüp Cağatayn

    2013-01-01

    Objective To report on general anesthesia management in amyotrophic lateral sclerosis. Case Presentation and Intervention A 47-year-old man presented with fracture of the humerus. The patient was diagnosed with amyotrophic lateral sclerosis. General anesthesia was induced with propofol, rocuronium and remifentanil. After uneventful surgical repair, TOF (train-of-four) ratio reached >0.90 at the end of operation. However, muscle strength and tidal volume were inadequate. After sugammadex 2 mg kg−1 i.v. was given, the patient was extubated 120 s later. Conclusion This case highlights that rocuronium and sugammadex can be used safely in patients with amyotrophic lateral sclerosis undergoing surgery with general anesthesia. PMID:23075763

  17. 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.

  18. The predictive value of respiratory function tests for non-invasive ventilation in amyotrophic lateral sclerosis

    OpenAIRE

    Tilanus, T. B. M.; Groothuis, J. T.; TenBroek-Pastoor, J. M. C.; Feuth, T. B.; Heijdra, Y. F.; Slenders, J. P. L.; Doorduin, J.; Van Engelen, B. G.; Kampelmacher, M. J.; Raaphorst, J.

    2017-01-01

    BACKGROUND: Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. The timing of referral to a home ventilation service (HVS), which is in part based on respiratory function tests, has shown room for improvement. It is currently unknown which respiratory function test predicts an appropriate timing of the initiation of NIV. METHODS: We analysed, retrospectively, serial data of five respiratory function tests: forced vital capacity...

  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. Cognitive and behavioural deficits associated with the orbitomedial prefrontal cortex in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Meier, Sandra L; Charleston, Alison J; Tippett, Lynette J

    2010-11-01

    Amyotrophic lateral sclerosis, a progressive disease affecting motor neurons, may variably affect cognition and behaviour. We tested the hypothesis that functions associated with orbitomedial prefrontal cortex are affected by evaluating the behavioural and cognitive performance of 18 participants with amyotrophic lateral sclerosis without dementia and 18 healthy, matched controls. We measured Theory of Mind (Faux Pas Task), emotional prosody recognition (Aprosodia Battery), reversal of behaviour in response to changes in reward (Probabilistic Reversal Learning Task), decision making without risk (Holiday Apartment Task) and aberrant behaviour (Neuropsychiatric Inventory). We also assessed dorsolateral prefrontal function, using verbal and written fluency and planning (One-touch Stockings of Cambridge), to determine whether impairments in tasks sensitive to these two prefrontal regions co-occur. The patient group was significantly impaired at identifying social faux pas, recognizing emotions and decision-making, indicating mild, but consistent impairment on most measures sensitive to orbitomedial prefrontal cortex. Significant levels of aberrant behaviour were present in 50% of patients. Patients were also impaired on verbal fluency and planning. Individual subject analyses involved computing classical dissociations between tasks sensitive to different prefrontal regions. These revealed heterogeneous patterns of impaired and spared cognitive abilities: 33% of participants had classical dissociations involving orbitomedial prefrontal tasks, 17% had classical dissociations involving dorsolateral prefrontal tasks, 22% had classical dissociations between tasks of both regions, and 28% had no classical dissociations. These data indicate subtle changes in behaviour, emotional processing, decision-making and altered social awareness, associated with orbitomedial prefrontal cortex, may be present in a significant proportion of individuals with amyotrophic lateral sclerosis

  1. Coping strategies among patients with newly diagnosed amyotrophic lateral sclerosis.

    Science.gov (United States)

    Jakobsson Larsson, Birgitta; Nordin, Karin; Askmark, Håkan; Nygren, Ingela

    2014-11-01

    To prospectively identify different coping strategies among newly diagnosed amyotrophic lateral sclerosis patients and whether they change over time and to determine whether physical function, psychological well-being, age and gender correlated with the use of different coping strategies. Amyotrophic lateral sclerosis is a fatal disease with impact on both physical function and psychological well-being. Different coping strategies are used to manage symptoms and disease progression, but knowledge about coping in newly diagnosed amyotrophic lateral sclerosis patients is scarce. This was a prospective study with a longitudinal and descriptive design. A total of 33 patients were included and evaluation was made at two time points, one to three months and six months after diagnosis. Patients were asked to complete the Motor Neuron Disease Coping Scale and the Hospital Anxiety and Depression Scale. Physical function was estimated using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale. The most commonly used strategies were support and independence. Avoidance/venting and information seeking were seldom used at both time points. The use of information seeking decreased between the two time points. Men did not differ from women, but patients ≤64 years used positive action more often than older patients. Amyotrophic Lateral Sclerosis Functional Rating Scale was positively correlated with positive action at time point 1, but not at time point 2. Patients' psychological well-being was correlated with the use of different coping strategies. Support and independence were the most used coping strategies, and the use of different strategies changed over time. Psychological well-being was correlated with different coping strategies in newly diagnosed amyotrophic lateral sclerosis patients. The knowledge about coping strategies in early stage of the disease may help the nurses to improve and develop the care and support for these patients. © 2014 John Wiley

  2. Respiratory exercise in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Pinto, Susana; Swash, Michael; de Carvalho, Mamede

    2012-01-01

    We have evaluated the potential role of respiratory exercise by implementing specific inspiratory muscle training in a selected population of early-affected amyotrophic lateral sclerosis (ALS) patients. We studied 26 patients with ALS with normal respiratory function using two groups of patients in a parallel, control-group, randomized, delayed-start design. Patients in the first group (G1) started the active inspiratory exercise programme at entry and were followed for eight months, while the second group (G2) of patients followed a placebo exercise programme for the first four months and then active exercise for the second four-month period. The primary outcome measure was the ALSFRS. Respiratory tests, neurophysiological measurements, fatigue and quality of life scales were secondary outcomes. Analysis of covariance was used to compare changes between and within groups. Results showed that there was no significant difference between the two patient groups. Within-group analysis suggested that inspiratory exercise promotes a transient improvement in the respiratory subscore and in the maximal voluntary ventilation, peak expiratory flow, and sniff inspiratory pressure. In conclusion, there was no clear positive or negative outcome of the respiratory exercise protocol we have proposed, but we cannot rule out a minor positive effect. Exercise regimes merit more detailed clinical evaluation in ALS.

  3. Amyotrophic lateral sclerosis: sonographic evaluation of dysphagia.

    Science.gov (United States)

    Tamburrini, S; Solazzo, A; Sagnelli, A; Del Vecchio, L; Reginelli, A; Monsorrò, M; Grassi, R

    2010-08-01

    The authors sought to determine the role of video ultrasonography (VUS) in the diagnostic assessment of dysphagia in patients with amyotrophic lateral sclerosis (ALS). Nine patients underwent simultaneous static and dynamic VUS examination and videofluoroscopy (VFS) of swallowing. At the static phase, VUS showed 5/9 patients had lingual atrophy. Abnormal bolus position was observed in 6/9 patients at VUS and 3/9 at VFS. Both techniques identified an inability to keep the bolus in the oral cavity in 4/9 patients. At the dynamic phase, reduced lingual movement was observed in 5/9 patients at VUS and 2/9 at VFS. Disorganised tongue movement was seen in 3/9 patients at VUS and in 2/9 at VFS. Fragmented swallowing was only visualised at VUS. Stagnation of ingested material was never visualised at VUS, whereas it was clearly depicted in 2/9 patients at VFS. VUS can be integrated into the diagnostic protocol for evaluating swallowing in patients with ALS, as it has higher sensitivity than VFS in assessing the dynamic factors that represent the early signs of dysphagia.

  4. Risk factors for amyotrophic lateral sclerosis

    Science.gov (United States)

    Ingre, Caroline; Roos, Per M; Piehl, Fredrik; Kamel, Freya; Fang, Fang

    2015-01-01

    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. PMID:25709501

  5. Amyotrophic Lateral Sclerosis: New Perpectives and Update

    Science.gov (United States)

    Orsini, Marco; Oliveira, Acary Bulle; Nascimento, Osvaldo J.M.; Reis, Carlos Henrique Melo; Leite, Marco Antonio Araujo; de Souza, Jano Alves; Pupe, Camila; de Souza, Olivia Gameiro; Bastos, Victor Hugo; de Freitas, Marcos R.G.; Teixeira, Silmar; Bruno, Carlos; Davidovich, Eduardo; Smidt, Benny

    2015-01-01

    Amyotrophic lateral sclerosis (ALS), Charcot’s disease or Lou Gehrig’s disease, is a term used to cover the spetrum of syndromes caracterized by progressive degeneration of motor neurons, a paralytic disorder caused by motor neuron degeneration. Currently, there are approximately 25,000 patients with ALS in the USA, with an average age of onset of 55 years. The incidence and prevalence of ALS are 1-2 and 4-6 per 100,000 each year, respectively, with a lifetime ALS risk of 1/600 to 1/1000. It causes progressive and cumulative physical disabilities, and leads to eventual death due to respiratory muscle failure. ALS is diverse in its presentation, course, and progression. We do not yet fully understand the causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. In this chapter, we will discuss the diagnosis, treatment, and how to cope with impaired function and end of life based on of our experience, guidelines, and clinical trials. Nowadays ALS seems to be a more complex disease than it did two decades – or even one decade – ago, but new insights have been plentiful. Clinical trials should be seen more as experiments on pathogenic mechanisms. A medication or combination of medications that targets more than one pathogenic pathway may slow disease progression in an additive or synergistic fashion. PMID:26487927

  6. Altered cortical communication in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Blain-Moraes, Stefanie; Mashour, George A; Lee, Heonsoo; Huggins, Jane E; Lee, Uncheol

    2013-05-24

    Amyotrophic lateral sclerosis (ALS) is a disorder associated primarily with the degeneration of the motor system. More recently, functional connectivity studies have demonstrated potentially adaptive changes in ALS brain organization, but disease-related changes in cortical communication remain unknown. We recruited individuals with ALS and age-matched controls to operate a brain-computer interface while electroencephalography was recorded over three sessions. Using normalized symbolic transfer entropy, we measured directed functional connectivity from frontal to parietal (feedback connectivity) and parietal to frontal (feedforward connectivity) regions. Feedback connectivity was not significantly different between groups, but feedforward connectivity was significantly higher in individuals with ALS. This result was consistent across a broad electroencephalographic spectrum (4-35 Hz), and in theta, alpha and beta frequency bands. Feedback connectivity has been associated with conscious state and was found to be independent of ALS symptom severity in this study, which may have significant implications for the detection of consciousness in individuals with advanced ALS. We suggest that increases in feedforward connectivity represent a compensatory response to the ALS-related loss of input such that sensory stimuli have sufficient strength to cross the threshold necessary for conscious processing in the global neuronal workspace. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Redox Regulation in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Parakh, Sonam; Spencer, Damian M.; Halloran, Mark A.; Soo, Kai Y.; Atkin, Julie D.

    2013-01-01

    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. PMID:23533690

  8. 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...

  9. 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

    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

  10. Tele-treatment of patients with amyotrophic lateral sclerosis (ALS)

    NARCIS (Netherlands)

    Oude Nijeweme-d'Hollosy, Wendy; Janssen, Emile P.F.; Huis in 't Veld, M.H.A.; Spoelstra, Jos; Vollenbroek-Hutten, Miriam Marie Rosé; Hermens, Hermanus J.

    2006-01-01

    Management of patients with amyotrophic lateral sclerosis (ALS) mainly consists of (psycho) social support and advice on activities of daily living. We evaluated the effects of tele-treatment in addition to the conventional method of care in four patients with ALS. A Web application was built with

  11. An Investigation of Perspectives of Respite Admission Among People Living With Amyotrophic Lateral Sclerosis and the Hospitals That Support Them.

    Science.gov (United States)

    Nakai, Michiko; Narita, Yugo; Tomimoto, Hidekazu

    2017-07-01

    Amyotrophic lateral sclerosis is a progressive disease with rapid degeneration. Respite care is an essential service for improving the well-being of both patients with this disease and their family caregivers, but accessibility of respite services is limited. This study investigates perspectives on respite admission among people living with amyotrophic lateral sclerosis and the hospitals supporting them. We conducted semistructured interviews among 3 patients with amyotrophic lateral sclerosis and 12 family members, exploring demographic information and their awareness and experience of respite admission. We also interviewed 16 representatives from hospitals about awareness of and preparation for respite admission for patients with this disease, the role of regional networks for intractable diseases, and knowledge about communication support schemes. We found significant differences in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale between patients who had and had not received respite admission. Qualitative analysis of the data indicated that respite admission was a contributory factor in continuing and stabilizing home care. Limited provision of social services and hospital care quality were barriers to respite admission. Respite admission was essential to continued home care for patients with amyotrophic lateral sclerosis. Severe-stage patients were eligible for respite admission. Its accessibility, however, was limited, especially for patients living in rural areas. Supporting hospitals had limited capacity to respond to patients' needs. Individualized care and communication were internal barriers to respite admission.

  12. 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

  13. 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.

  14. [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.

  15. 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

  16. Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia.

    Science.gov (United States)

    Mishra, Pooja-Shree; Vijayalakshmi, K; Nalini, A; Sathyaprabha, T N; Kramer, B W; Alladi, Phalguni Anand; Raju, T R

    2017-12-16

    Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated. We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-α, IL-6, IFN-γ, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures. We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-α, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-γ was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells. Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory

  17. Cortical influences drive amyotrophic lateral sclerosis.

    Science.gov (United States)

    Eisen, Andrew; Braak, Heiko; Del Tredici, Kelly; Lemon, Roger; Ludolph, Albert C; Kiernan, Matthew C

    2017-11-01

    The early motor manifestations of sporadic amyotrophic lateral sclerosis (ALS), while rarely documented, reflect failure of adaptive complex motor skills. The development of these skills correlates with progressive evolution of a direct corticomotoneuronal system that is unique to primates and markedly enhanced in humans. The failure of this system in ALS may translate into the split hand presentation, gait disturbance, split leg syndrome and bulbar symptomatology related to vocalisation and breathing, and possibly diffuse fasciculation, characteristic of ALS. Clinical neurophysiology of the brain employing transcranial magnetic stimulation has convincingly demonstrated a presymptomatic reduction or absence of short interval intracortical inhibition, accompanied by increased intracortical facilitation, indicating cortical hyperexcitability. The hallmark of the TDP-43 pathological signature of sporadic ALS is restricted to cortical areas as well as to subcortical nuclei that are under the direct control of corticofugal projections. This provides anatomical support that the origins of the TDP-43 pathology reside in the cerebral cortex itself, secondarily in corticofugal fibres and the subcortical targets with which they make monosynaptic connections. The latter feature explains the multisystem degeneration that characterises ALS. Consideration of ALS as a primary neurodegenerative disorder of the human brain may incorporate concepts of prion-like spread at synaptic terminals of corticofugal axons. Further, such a concept could explain the recognised widespread imaging abnormalities of the ALS neocortex and the accepted relationship between ALS and frontotemporal dementia. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  18. Nutritional intervention for amyotrophic lateral sclerosis.

    Science.gov (United States)

    Morassutti, I; Giometto, M; Baruffi, C; Marcon, M L; Michieletto, S; Giometto, B; Spinella, N; Paccagnella, A

    2012-09-01

    The aim of the study was to assess the consequences of early and systematic nutritional intervention on the clinical conditions of amyotrophic lateral sclerosis (ALS) patients and on the opportunity to maintain a good nutritional status for as long as possible. Thirty-three subjects with ALS. Protocol Group: 12 subjects (9 M and 3 F) monitored according to a precise nutritional intervention protocol. 21 subjects (10 M and 11 F) monitored before applying the protocol. Data recorded at the time of initial assessment were compared and expressed as the mean ± standard deviation for the Protocol Group vs. the BMI (kg/m2) 23.6 ± 4.1 vs. 21.6 ± 3.5; weight loss as a percentage of usual weight 6.6 ± 7.9 vs. 16.3 ± 8.8 (P=0.003). At six months: weight loss as a percentage of usual weight 4.9 ± 6.2 vs. 16.9 ± 10.2 (P=0.002). At 12 months: weight loss as a percentage of usual weight 7.3 ± 7.1 vs. 17.5 ± 11.1 (P=0.03). At the first follow-up visit, fewer patients in the Protocol Group were receiving enteral nutrition (25%) than patients in the CONTROL GROUP (60%). At six-month follow-up visit: 30% vs. 68%. Standard enteral nutrition formulas were used. One year after initial assessment, the mortality rate was 17% for the Protocol Group, whereas it was 24% at six months and 33% after one year for the CONTROL GROUP. If patients are treated before any significant weight loss occurs, early and specific nutritional intervention allows good nutritional status to be maintained for a longer period; if artificial nutrition is required, standard diets are able to ensure adequate clinical results.

  19. 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.

  20. [Clinical polymorphism of amyotrophic lateral sclerosis].

    Science.gov (United States)

    Kovrazhkina, E A; Razinskaya, O D; Gubsky, L V

    To clarify clinical polymorphism of amyotrophic lateral sclerosis (ALS). The study was based on records of a hospital personalized register. Ninety-four patients, aged from 25 to 81 years, diagnosed with ALS according to El Escorial criteria were included. Electromyography and, if necessary, transcranial magnetic stimulation and magnetic-resonance tomography were used to confirm the diagnosis. Disease progression was assessed with the ARSFRS. Age at disease onset, progression rate and duration of survival of patients, rare symptoms of ALS ('extramotor'), time for palliative care (gastrostomy, non-invasive and invasive lung ventilation) and provision of the care to the patient, family history were recorded in a specially designed questionnaire. Most of the patients had sporadic ALS, only two familial cases were identified. Spinal onset ALS was found in 66.0% of the patients, bulbar onset in 29.8%, diffuse onset (spinal and bulbar motor neurons were affected simultaneously) in 4.2%. Moderate ALS progression was observed in 42.6% of the patients, mean time till death was 3.0±1.2 years. A slow progression was found in patients with cervical, low back and bulbar onset. A rapid and even 'momentary' type of progression was in diffuse and breast onset. An extremely slow progression with the long-term hospital treatment and survival >5 years was found in 9.7%. Rare ALS symptoms were represented by specific cognitive and psychological impairments, a type of frontal/temporal dysfunction, but only 5 (5.3%) patients were diagnosed with ALS-dementia. Signs of pathological muscle fatigue (myasthenic syndrome) were identified in 18 (19.1%), extrapyramidal disorders in 5 (5.3%), coordination disorders in 4 (4.3%), pain in 12 (12.8%), sensory symptoms in 5 (5.3%) of the patients. ALS is a multisystemic neurodegeneration disease though the progressive motor neuron death determines the fatal outcome.

  1. 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...

  2. Axonal excitability properties in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Vucic, Steve; Kiernan, Matthew C

    2006-07-01

    To investigate axolemmal ion channel function in patients diagnosed with sporadic amyotrophic lateral sclerosis (ALS). A recently described threshold tracking protocol was implemented to measure multiple indices of axonal excitability in 26 ALS patients by stimulating the median motor nerve at the wrist. The excitability indices studied included: stimulus-response curve (SR); strength-duration time constant (tauSD); current/threshold relationship; threshold electrotonus to a 100 ms polarizing current; and recovery curves to a supramaximal stimulus. Compound muscle action potential (CMAP) amplitudes were significantly reduced in ALS patients (ALS, 2.84+/-1.17 mV; controls, 8.27+/-1.09 mV, P<0.0005) and the SR curves for both 0.2 and 1 ms pulse widths were shifted in a hyperpolarized direction. Threshold electrotonus revealed a greater threshold change to both depolarizing and hyperpolarizing conditioning stimuli, similar to the 'fanned out' appearance that occurs with membrane hyperpolarization. The tauSD was significantly increased in ALS patients (ALS, 0.50+/-0.03 ms; controls, 0.42+/-0.02 ms, P<0.05). The recovery cycle of excitability following a conditioning supramaximal stimulus revealed increased superexcitability in ALS patients (ALS, 29.63+/-1.25%; controls, 25.11+/-1.01%, P<0.01). Threshold tracking studies revealed changes indicative of widespread dysfunction in axonal ion channel conduction, including increased persistent Na+ channel conduction, and abnormalities of fast paranodal K+ and internodal slow K+ channel function, in ALS patients. An increase in persistent Na+ conductances coupled with reduction in K+ currents would predispose axons of ALS patients to generation of fasciculations and cramps. Axonal excitability studies may provide insight into mechanisms responsible for motor neuron loss in ALS.

  3. Structures of the G85R Variant of SOD1 in Familial Amyotrophic Lateral Sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Xiaohang; Antonyuk, Svetlana V.; Seetharaman, Sai V.; Whitson, Lisa J.; Taylor, Alexander B.; Holloway, Stephen P.; Strange, Richard W.; Doucette, Peter A.; Valentine, Joan Selverstone; Tiwari, Ashutosh; Hayward, Lawrence J.; Padua, Shelby; Cohlberg, Jeffrey A.; Hasnain, S. Samar; Hart, P. John (Texas-HSC); (Cal. State); (UMASS, MED); (UCLA); (Daresbury)

    2008-07-21

    Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause a dominant form of the progressive neurodegenerative disease amyotrophic lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant develop paralytic symptoms concomitant with the appearance of SOD1-enriched proteinaceous inclusions in their neural tissues. The process(es) through which misfolding or aggregation of G85R SOD1 induces motor neuron toxicity is not understood. Here we present structures of the human G85R SOD1 variant determined by single crystal x-ray diffraction. Alterations in structure of the metal-binding loop elements relative to the wild type enzyme suggest a molecular basis for the metal ion deficiency of the G85R SOD1 protein observed in the central nervous system of transgenic mice and in purified recombinant G85R SOD1. These findings support the notion that metal-deficient and/or disulfide-reduced mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral sclerosis.

  4. The P413L chromogranin B variation in French patients with sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Blasco, Hélène; Corcia, Philippe; Veyrat-Durebex, Charlotte; Coutadeur, Cathleen; Fournier, Clémentine; Camu, William; Gordon, Paul; Praline, Julien; Andres, Christian R; Vourc'h, Patrick

    2011-05-01

    Chromogranins interact with mutant forms of superoxide dismutase 1 (SOD1) responsible for a portion of familial amyotrophic lateral sclerosis (ALS). A particular variation (P413L) in the chromogranin B gene, CHGB, has been recently associated with an earlier age at onset in both familial and sporadic ALS. The aim of our study was to evaluate the P413L chromogranin variation in French patients with sporadic amyotrophic lateral sclerosis. We developed a High Resolution DNA Melting (HRM) protocol to analyse the P413L variation in the CHGB gene in 540 French patients with sporadic ALS and 504 controls. The clinical characteristics of patients were analysed in relation to their genotype. Results showed that our study on a large cohort of French-Caucasian patients with SALS and controls failed to confirm an increased frequency of the 413L variant in SALS patients. This frequency was 5.3% in the SALS population and 5.5% in the control group. Moreover, we did not observe a previous observation of a difference of age at onset between T-allele carriers and non-carriers (median age of onset 60.4 vs. 62.0 years of age, respectively). Thus, our findings do not support the 413L variant of rs742710 as a risk factor for sporadic ALS in the French population.

  5. 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.

  6. 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

  7. [Virus-like inclusions in the myocytes of the skeletal muscle in lateral amyotrophic sclerosis].

    Science.gov (United States)

    Musaeva, L S; Sakharova, A V; Zavalishin, I A

    2004-01-01

    Microscopic examination of musculus gastrocnemius biopsies was made in four cases of sporadic lateral amyotrophic sclerosis (LAS). The validity of the clinical diagnosis was confirmed by detected neurotrophic atrophy of the muscular fibers typical for LAS. Electron microscopic study revealed virus-like inclusions 200-450 nm in size in sarcoplasm of myocytes of all the patients. The inclusions consist of lined cells of hexagonal shape at the distance of 37-41 nm from each other. The inclusions resemble enteroviruses but are not identical to them both by size and structure of their elements. There were also specific ultrastructural changes of myocytes corresponding to viral infection. The above virus-like inclusions should be considered as specific structures formed as a result of metabolic shifts caused by productive action on the cell of infective or unknown factor.

  8. 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

    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

  9. 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

  10. MUSCLE-FIBER CONDUCTION-VELOCITY IN AMYOTROPHIC-LATERAL-SCLEROSIS AND TRAUMATIC LESIONS OF THE PLEXUS BRACHIALIS

    NARCIS (Netherlands)

    VANDERHOEVEN, JH; ZWARTS, MJ; VANWEERDEN, TW

    1993-01-01

    Muscle fiber conduction velocity (MFCV) in biceps brachii was studied in traumatic brachial plexus lesions (16 patients) and amyotrophic lateral sclerosis (ALS) (22 patients) by means of an invasive (S-MFCV) and a surface (S-MFCV) method. After complete denervation an exponential decrease of the

  11. 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 ...

  12. MRI and SPECT findings in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Ukada, F.; Sawada, H.; Seriu, N.; Shindou, K.; Nishitani, N.; Kameyama, M.

    1992-01-01

    MRI was performed in 21 patients and single photon emission computed tomography (SPECT) with N-isopropyl-p- 123 I iodoamphetamine in 16 patients, to visualize upper motor neurone lesions in amyotrophic lateral sclerosis. T2-weighted MRI revealed high signal along the course of the pyramidal tract in the internal capsule and cerebral peduncle in 4 of 21 patients. SPECT images were normal in 4 patients, but uptake was reduced in the cerebral cortex that includes the motor area in 11. (orig.)

  13. Tracheomegaly Secondary to Tracheotomy Tube Cuff in Amyotrophic Lateral Sclerosis

    OpenAIRE

    Lee, Dong Hoon; Yoon, Tae Mi; Lee, Joon Kyoo; Lim, Sang Chul

    2015-01-01

    Abstract Tracheomegaly has not been reported in amyotrophic lateral sclerosis (ALS). Herein, the authors report a case of tracheomegaly secondary to tracheotomy tube cuff in a patient with ALS. To our knowledge, this is the first report of an ALS patient with tracheomegaly and of tracheomegaly being associated with tracheotomy tube cuff and home tracheotomy mechanical ventilator. The clinician should consider the possibility of tracheomegaly in the differential diagnosis, if a patient with AL...

  14. Cortical Thinning and Clinical Heterogeneity in Amyotrophic Lateral Sclerosis

    OpenAIRE

    Mezzapesa, Domenico Maria; D?Errico, Eustachio; Tortelli, Rosanna; Distaso, Eugenio; Cortese, Rosa; Tursi, Marianna; Federico, Francesco; Zoccolella, Stefano; Logroscino, Giancarlo; Dicuonzo, Franca; Simone, Isabella Laura

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) has heterogeneous clinical features that could be translated into specific patterns of brain atrophy. In the current study we have evaluated the relationship between different clinical expressions of classical ALS and measurements of brain cortical thickness. Cortical thickness analysis was conducted from 3D-MRI using FreeSurfer software in 29 ALS patients and 20 healthy controls. We explored three clinical traits of the disease, subdividing the patients in...

  15. Laryngeal response patterns influence the efficacy of mechanical assisted cough in amyotrophic lateral sclerosis.

    OpenAIRE

    Andersen, Tiina Maarit; Sandnes, Astrid; Brekka, Anne Kristine; Hilland, Magnus; Clemm, Hege; Fondenes, Ove; Tysnes, Ole Bjørn; Heimdal, John-Helge; Halvorsen, Thomas; Vollsæter, Maria; Røksund, Ola Drange

    2016-01-01

    Background: Most patients with amyotrophic lateral sclerosis (ALS) are treated with mechanical insufflation–exsufflation (MI-E) in order to improve cough. This method often fails in ALS with bulbar involvement, allegedly due to upper-airway malfunction. We have studied this phenomenon in detail with laryngoscopy to unravel information that could lead to better treatment. Methods: We conducted a cross-sectional study of 20 patients with ALS and 20 healthy age-matched and sex-matched v...

  16. Noninvasive ventilation reduces energy expenditure in amyotrophic lateral sclerosis

    OpenAIRE

    Georges , Marjolaine; Morélot-Panzini , Capucine; Similowski , Thomas; Gonzalez-Bermejo , Jesus

    2014-01-01

    International audience; BackgroundAmyotrophic lateral sclerosis (ALS) leads to chronic respiratory failure. Diaphragmatic dysfunction, a major driver of dyspnea and mortality, is associated with a shift of the burden of ventilation to extradiaphragmatic inspiratory muscles, including neck muscles. Besides, energy expenditure is often abnormally high in ALS, and this is associated with a negative prognostic value. We hypothesized that noninvasive ventilation (NIV) would relieve inspiratory nec...

  17. Exposing asymmetric gray matter vulnerability in amyotrophic lateral sclerosis

    OpenAIRE

    Devine, Matthew S.; Pannek, Kerstin; Coulthard, Alan; McCombe, Pamela A.; Rose, Stephen E.; Henderson, Robert D.

    2015-01-01

    Limb weakness in amyotrophic lateral sclerosis (ALS) is typically asymmetric. Previous studies have identified an effect of limb dominance on onset and spread of weakness, however relative atrophy of dominant and non-dominant brain regions has not been investigated. Our objective was to use voxel-based morphometry (VBM) to explore gray matter (GM) asymmetry in ALS, in the context of limb dominance. 30 ALS subjects were matched with 17 healthy controls. All subjects were right-handed. Each und...

  18. Amyotrophic Lateral Sclerosis Multiprotein Biomarkers in Peripheral Blood Mononuclear Cells

    OpenAIRE

    Nardo, Giovanni; Pozzi, Silvia; Pignataro, Mauro; Lauranzano, Eliana; Spano, Giorgia; Garbelli, Silvia; Mantovani, Stefania; Marinou, Kalliopi; Papetti, Laura; Monteforte, Marta; Torri, Valter; Paris, Luca; Bazzoni, Gianfranco; Lunetta, Christian; Corbo, Massimo

    2011-01-01

    Background 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. Methodology/Principal Findings We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel...

  19. 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 ...

  20. 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.

  1. 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.

  2. Manganese concentration in the spinal cords and blood corpuscles of amyotrophic lateral sclerosis patients

    Energy Technology Data Exchange (ETDEWEB)

    Miyata, Satoru; Toyoshima, Masanori; Otsuki, Yuzo; Nagata, Hiroshi; Nakamura, Shigenobu (Kyoto Univ. (Japan). Faculty of Medicine)

    1981-11-01

    Manganese concentration in the spinal cord tissues and the blood corpuscles from patients with amyotrophic lateral sclerosis (ALS) and other diseases were measured by neutron activation analysis. The mean manganese concentration in the spinal cord from ALS patients was significantly higher than that from control subjects, especially in the anterior horn of the cervical cord. In order to determine the manganese concentration in blood corpuscles by neutron activation analysis, it was necessary to subtract /sup 56/Mn derived from the /sup 56/Fe(n, p)/sup 56/Mn reaction. The mean Mn concentration in the blood corpuscles from ALS patients seems to be lower than that from patients with other diseases. Fe, Se, Rb and Zn concentrations in the blood corpuscles from ALS patients were not different from those of patients with other diseases.

  3. Manganese concentration in the spinal cords and blood corpuscles of amyotrophic lateral sclerosis patients

    International Nuclear Information System (INIS)

    Miyata, Satoru; Toyoshima, Masanori; Otsuki, Yuzo; Nagata, Hiroshi; Nakamura, Shigenobu

    1981-01-01

    Manganese concentration in the spinal cord tissues and the blood corpuscles from patients with amyotrophic lateral sclerosis (ALS) and other diseases were measured by neutron activation analysis. The mean manganese concentration in the spinal cord from ALS patients was significantly higher than that from control subjects, especially in the anterior horn of the cervical cord. In order to determine the manganese concentration in blood corpuscles by neutron activation analysis, it was necessary to subtract 56 Mn derived from the 56 Fe(n, p) 56 Mn reaction. The mean Mn concentration in the blood corpuscles from ALS patients seems to be lower than that from patients with other diseases. Fe, Se, Rb and Zn concentrations in the blood corpuscles from ALS patients were not different from those of patients with other diseases. (author)

  4. Diffusion tensor tract-specific analysis of the uncinate fasciculus in patients with amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Sato, Kanako; Masutani, Yoshitaka; Watadani, Takeyuki; Nakata, Yasuhiro; Yoshida, Mariko; Abe, Osamu; Ohtomo, Kuni [University of Tokyo, Department of Radiology, Graduate School of Medicine, Bunkyo, Tokyo (Japan); Aoki, Shigeki [Juntendo University, Department of Radiology, Bunkyo, Tokyo (Japan); Iwata, Nobue K.; Terao, Yasuo; Tsuji, Shoji [University of Tokyo, Department of Neurology, Graduate School of Medicine, Bunkyo, Tokyo (Japan)

    2010-08-15

    The uncinate fasciculus (UF) consists of core fibers connecting the frontal and temporal lobes and is considered to be related to cognitive/behavioral function. Using diffusion tensor tractography, we quantitatively evaluated changes in fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) of the UF by tract-specific analysis to evaluate the damage of the UF in patients with amyotrophic lateral sclerosis (ALS). We obtained diffusion tensor images of 15 patients with ALS and 9 age-matched volunteers. Patients with ALS showed significantly lower mean FA (P = 0.029) compared with controls. No significant difference was seen in mean ADC. The results suggest that damage of the UF in patients with ALS can be quantitatively evaluated with FA. (orig.)

  5. [Value of split hand in the differential diagnosis of amyotrophic lateral sclerosis and cervical spondylotic amyotrophy].

    Science.gov (United States)

    Jiang, M; Yan, X; Yan, L R; Zhan, Y B; Hu, H T

    2017-12-19

    Objective: To investigate the value of split hand in the differential diagnosis of amyotrophic lateral sclerosis(ALS) and cervical spondylotic amyotrophy (CSA). Methods: A total of 62 ALS patients, 57 CSA patients and 65 normal controls who visited the Neurology and Spine Department of Beijing Jishuitan Hospital from May 2013 to June 2017 were enrolled into this study.The amplitudes of compound muscle action potentials (CMAP) were recorded from abductor digiti minimi (ADM) and abductor pollicis brevis (APB). Moreover, the ratio of CMAP amplitude between ADM and APB (ADM/APB) was calculated. Results: The ADM/APB of the ALS group (1.93±1.97)was significantly higher than that of the normal control group (0.92±0.22)( P differentiation of ALS and CSA.

  6. Shortcomings in the Current Amyotrophic Lateral Sclerosis Trials and Potential Solutions for Improvement

    Directory of Open Access Journals (Sweden)

    Nakul Katyal

    2017-09-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a clinically progressive neurodegenerative syndrome predominantly affecting motor neurons and their associated tracts. Riluzole and edaravone are the only FDA certified drugs for treating ALS. Over the past two decades, almost all clinical trials aiming to develop a successful therapeutic strategy for this disease have failed. Genetic complexity, inadequate animal models, poor clinical trial design, lack of sensitive biomarkers, and diagnostic delays are some of the potential reasons limiting any significant development in ALS clinical trials. In this review, we have outlined the possible reasons for failure of ALS clinical trials, addressed the factors limiting timely diagnosis, and suggested possible solutions for future considerations for each of the shortcomings.

  7. Anterior cysts of the spine: a difficult differential diagnosis to amyotrophic lateral sclerosis.

    Science.gov (United States)

    Schmalbach, S; Petri, S; Götz, F; Dengler, R; Krampfl, K

    2008-11-01

    We describe three patients referred to our ALS/MND clinic with suspected diagnosis of amyotrophic lateral sclerosis (ALS). The patients were all male, middle aged, and their initial symptoms were weakness and fasciculations in upper limb muscles. Results of clinical and electrophysiological examination in all cases were in accordance with possible ALS according to the revised El Escorial criteria. Other conditions mimicking ALS appeared to be excluded by extensive technical examinations and laboratory tests. Only repeated MRI examinations revealed anterior spinal cysts several years after symptom onset. This report intends to highlight this rare and difficult differential diagnosis of ALS and underlines the value of the revised El Escorial criteria in conjunction with electrophysiology to asses the certainty of the diagnosis ALS.

  8. Mindfulness as a Protective Factor for the Burden of Caregivers of Amyotrophic Lateral Sclerosis Patients.

    Science.gov (United States)

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

    2016-01-01

    Caregivers of people with severe chronic conditions, such as amyotrophic lateral sclerosis (ALS), are at risk of developing depression and anxiety and reduced quality of life. Few studies have explored protective factors in this population and none investigated the role of mindfulness. The study aimed to examine the relationship between mindfulness and health-related outcomes in a population of ALS caregivers. We conducted an online survey with ALS caregivers, and again at 4-month follow-up, to assess mindfulness, burden, quality of life, anxiety, and depression. The associations between mindfulness and the other outcomes were evaluated both cross-sectionally and longitudinally. Mindfulness correlated negatively with burden, depression, and anxiety and positively with quality of life, maintaining stability through time. Our results showed that mindfulness is positively related to quality of life and negatively related to level of burden. We suggest that this construct can represent a preventative factor toward the negative effects of caregiving. © 2015 Wiley Periodicals, Inc.

  9. The experience of meditation for people with amyotrophic lateral sclerosis and their caregivers - a qualitative analysis.

    Science.gov (United States)

    Marconi, Anna; Gragnano, Gaia; Lunetta, Christian; Gatto, Ramona; Fabiani, Viviana; Tagliaferri, Aurora; Rossi, Gabriella; Sansone, Valeria; Pagnini, Francesco

    2016-09-01

    There is a lack of studies about psychological interventions for people with amyotrophic lateral sclerosis (ALS) and their caregivers. We investigated the experience of a meditation training program tailored for ALS needs. People with ALS (pALS) and their caregivers that joined a meditation program for ALS were interviewed at the end of the program. Verbatims were analyzed with a qualitative approach. Both pALS and their caregivers reported a positive impact on their psychological well-being, promoted by an increase in acceptance and non-judgmental attitude. Furthermore, coping strategies seem to improve, with a positive effect on resilience skills. The ALS meditation training program seems to be an effective psychological intervention for the promotion of well-being in pALS and their caregivers.

  10. Emerging understanding of the genotype-phenotype relationship in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Goutman, Stephen A; Chen, Kevin S; Paez-Colasante, Ximena; Feldman, Eva L

    2018-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive, noncurable neurodegenerative disorder of the upper and lower motor neurons causing weakness and death within a few years of symptom onset. About 10% of patients with ALS have a family history of the disease; however, ALS-associated genetic mutations are also found in sporadic cases. There are over 100 ALS-associated mutations, and importantly, several genetic mutations, including C9ORF72, SOD1, and TARDBP, have led to mechanistic insight into this complex disease. In the clinical realm, knowledge of ALS genetics can also help explain phenotypic heterogeneity, aid in genetic counseling, and in the future may help direct treatment efforts. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis?

    Science.gov (United States)

    Kabashi, Edor; Valdmanis, Paul N; Dion, Patrick; Rouleau, Guy A

    2007-12-01

    The identification in 1993 of superoxide dismutase-1 (SOD1) mutations as the cause of 10 to 20% of familial amyotrophic lateral sclerosis cases, which represents 1 to 2% of all amyotrophic lateral sclerosis (ALS) cases, prompted a substantial amount of research into the mechanisms of SOD1-mediated toxicity. Recent experiments have demonstrated that oxidation of wild-type SOD1 leads to its misfolding, causing it to gain many of the same toxic properties as mutant SOD1. In vitro studies of oxidized/misfolded SOD1 and in vivo studies of misfolded SOD1 have indicated that these protein species are selectively toxic to motor neurons, suggesting that oxidized/misfolded SOD1 could lead to ALS even in individuals who do not carry an SOD1 mutation. It has also been reported that glial cells secrete oxidized/misfolded mutant SOD1 to the extracellular environment, where it can trigger the selective death of motor neurons, offering a possible explanation for the noncell autonomous nature of mutant SOD1 toxicity and the rapid progression of disease once the first symptoms develop. Therefore, considering that sporadic (SALS) and familial ALS (FALS) cases are clinically indistinguishable, the toxic properties of mutated SOD1 are similar to that of oxidized/misfolded wild-type SOD1 (wtSOD1), and secreted/extracellular misfolded SOD1 is selectively toxic to motor neurons, we propose that oxidized/misfolded SOD1 is the cause of most forms of classic ALS and should be a prime target for the design of ALS treatments.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Spatial analysis of the etiology of amyotrophic lateral sclerosis among 1991 Gulf War veterans.

    Science.gov (United States)

    Miranda, Marie Lynn; Alicia Overstreet Galeano, M; Tassone, Eric; Allen, Kelli D; Horner, Ronnie D

    2008-11-01

    Veterans of the 1991 Gulf War have an increased risk of amyotrophic lateral sclerosis (ALS), but the etiology is unknown. This study sought to identify geographic areas with elevated risk for the later development of ALS among military personnel who served in the first Gulf War. A unified geographic information system (GIS) was constructed to allow analysis of secondary data on troop movements in the 1991 Gulf War theatre in the Persian Gulf region including Iraq, northern Saudi Arabia, and Kuwait. We fit Bayesian Poisson regression models to adjust for potential risk factors, including one relatively discrete environmental exposure, and to identify areas associated with elevated risk of ALS. We found that service in particular locations of the Gulf was associated with an elevated risk for later developing ALS, both before and after adjustment for branch of service and potential of exposure to chemical warfare agents in and around Khamisiyah, Iraq. Specific geographic locations of troop units within the 1991 Gulf War theatre are associated with an increased risk for the subsequent development of ALS among members of those units. The identified spatial locations represent the logical starting points in the search for potential etiologic factors of ALS among Gulf War veterans. Of note, for locations where the relative odds of subsequently developing ALS are among the highest, specific risk factors, whether environmental or occupationally related, have not been identified. The results of spatial models can be used to subsequently look for risk factors that follow the spatial pattern of elevated risk.

  14. 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...

  15. 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

  16. 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.

  17. Lead content of neuromuscular tissue in amyotrophic lateral sclerosis: case report and other considerations

    Energy Technology Data Exchange (ETDEWEB)

    Petkau, A; Sawatzky, A; Hillier, C R; Hoogstraten, J

    1974-10-01

    In a case of amyotrophic lateral sclerosis in which occupational history and laboratory evidence indicated that exposure to lead had occurred, it was found at necropsy that in nerve, spinal cord, and cardiac and skeletal muscle tissues the lead content was abnormally high. Significantly elevated levels of lead were also found however, in nerve, spinal cord and muscle tissue in other cases of amyotrophic lateral sclerosis that had not been exposed to lead during life. A reassessment of the role of lead in amyotrophic lateral sclerosis is indicated. (CIS Abstract Vol. 2)

  18. Atypical Initial Presentation of Painful Muscle Cramps in a Patient with Amyotrophic Lateral Sclerosis: A Case Report and Brief Review of the Literature.

    Science.gov (United States)

    Kuzel, Aaron R; Lodhi, Muhammad Uzair; Syed, Intekhab Askari; Rahim, Mustafa

    2017-11-10

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized clinically by progressive muscle weakness that can occur proximally or distally in either the upper or lower extremities. It includes both upper motor neuron signs (spasticity, hyperreflexia, clonus, and Babinski sign) and lower motor neuron signs (atrophy, weakness, and muscle fasciculation). Initial presentation of progressively painful muscle cramps should lead the physician to screen for other signs of amyotrophic lateral sclerosis. We report the case of a 51-year-old male, who presented with dull muscle cramps in the right upper shoulder and arm. After a careful history and physical exam, it was found that patient had both upper and lower motor neuron signs; therefore, a diagnosis of amyotrophic lateral sclerosis was made. Amyotrophic lateral sclerosis should strongly be considered in the differential diagnosis of patients presenting with an atypical initial presentation of progressively painful muscle cramps.

  19. “Neuropathology of amyotrophic lateral sclerosis and its variants”

    Science.gov (United States)

    Saberi, Shahram; Stauffer, Jennifer E.; Schulte, Derek J.; Ravits, John

    2015-01-01

    Summary Amyotrophic lateral sclerosis (ALS) is a clinical syndrome named for its neuropathological hallmark: degeneration of motor neurons in the spinal anterior horn and motor cortex and loss of axons in the lateral columns of the spinal cord. The signature neuropathological molecular signature common to almost all sporadic ALS and most familial ALS is TDP-43 immunoreactive neuronal cytoplasmic inclusions. The neuropathological and molecular neuropathological features of ALS variants primarly lateral sclerosis and progressive muscular atrophy are less certain, but also appear to share the primary features of ALS. A number of genetic causes including mutations in SOD1, FUS, and C9orf72 comprise a disease spectrum and all demonstrate distinctive molecular and neuropathological signatures. Neuropathology will continue to play to a key role in solving the puzzle of ALS pathogenesis. PMID:26515626

  20. 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...

  1. The genotype-phenotype landscape of familial amyotrophic lateral sclerosis in Australia.

    Science.gov (United States)

    McCann, E P; Williams, K L; Fifita, J A; Tarr, I S; O'Connor, J; Rowe, D B; Nicholson, G A; Blair, I P

    2017-09-01

    Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype-phenotype correlations. We report 60.8% of Australian ALS families in this cohort harbour a known ALS mutation. Hexanucleotide repeat expansions in C9orf72 accounted for 40.6% of families and 2.9% of sporadic patients. We also report ALS families with mutations in SOD1 (13.7%), FUS (2.4%), TARDBP (1.9%), UBQLN2 (.9%), OPTN (.5%), TBK1 (.5%) and CCNF (.5%). We present genotype-phenotype correlations between these genes as well as between gene mutations. Notably, C9orf72 hexanucleotide repeat expansion positive patients experienced significantly later disease onset than ALS mutation patients. Among SOD1 families, p.I114T positive patients had significantly later onset and longer survival. Our report highlights a unique spectrum of ALS gene frequencies among patients from the Australian population, and further, provides correlations between specific ALS mutations with disease onset and/or duration. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. The Utility of the Laboratory Work Up at the Time of Diagnosis of Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Mirian, Ario; Korngut, Lawrence

    2018-01-01

    Serological testing is routinely performed in the work up for a diagnosis of Amyotrophic Lateral Sclerosis (ALS) to exclude pathologies with similar clinical phenotypes. To determine the proportion of serological workup that changes the primary diagnosis and/or clinical management for patients presenting with signs of ALS. A retrospective chart review was conducted on patients from the Calgary Neuromuscular Intake Clinic in which the neurologist working diagnosis post-assessment is ALS. Charts from 2012 to 2016 with completed standard serological workup were reviewed. The proportion of abnormal results per investigation was determined and whether it resulted in a change in diagnosis and/or clinical management. A total of 276 charts were reviewed and 85 met full inclusion criteria. Serum creatine kinase (35%), vitamin B12 (18%), complete blood count with differential (11%), and parathyroid hormone (10%) were the among the investigations that had a proportion of abnormal results greater than 5%. Only 6% of patients had an abnormal result that qualified for a change in their clinical management none of which changed the primary diagnosis of ALS. Standard serological investigations in the work-up for a patient with ALS may have low utility from a diagnostic and management perspective.

  3. The eye-tracking computer device for communication in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Spataro, R; Ciriacono, M; Manno, C; La Bella, V

    2014-07-01

    To explore the effectiveness of communication and the variables affecting the eye-tracking computer system (ETCS) utilization in patients with late-stage amyotrophic lateral sclerosis (ALS). We performed a telephone survey on 30 patients with advanced non-demented ALS that were provisioned an ECTS device. Median age at interview was 55 years (IQR = 48-62), with a relatively high education (13 years, IQR = 8-13). A one-off interview was made and answers were later provided with the help of the caregiver. The interview included items about demographic and clinical variables affecting the daily ETCS utilization. The median time of ETCS device possession was 15 months (IQR = 9-20). The actual daily utilization was 300 min (IQR = 100-720), mainly for the communication with relatives/caregiver, internet surfing, e-mailing, and social networking. 23.3% of patients with ALS (n = 7) had a low daily ETCS utilization; most reported causes were eye-gaze tiredness and oculomotor dysfunction. Eye-tracking computer system is a valuable device for AAC in patients with ALS, and it can be operated with a good performance. The development of oculomotor impairment may limit its functional use. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Amyotrophic lateral sclerosis (ALS): three letters that change the people's life. For ever.

    Science.gov (United States)

    Oliveira, Acary Souza Bulle; Pereira, Roberto Dias Batista

    2009-09-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. Currently, we rely on a multidisciplinary approach to symptomatically manage and care for patients who have ALS. Although amyotrophic lateral sclerosis and its variants are readily recognized by neurologists, about 10% of patients are misdiagnosed, and delays in diagnosis are common. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and their family, and a positive care plan are prerequisites for good clinical management. A multidisciplinary, palliative approach can prolong survival and maintain quality of life. Treatment with Riluzole improves survival but has a marginal effect on the rate of functional deterioration, whereas non-invasive ventilation prolongs survival and improves or maintains quality of life. In this review, we discuss the diagnosis, management, and how to cope with impaired function and end of life on the basis of our experience, the opinions of experts, existing guidelines, and clinical trials. Multiple problems require a multidisciplinary approach including aggressive symptomatic management, rehabilitation to maintain motor function, nutritional support (enteric feeding, gastrostomy), respiratory support (non invasive home ventilation, invasive ventilation, tracheotomy), augmentative communication devices, palliative care, psychological support for both patients and families (because family members so often play a central role in management and care), communication between the care team, the patient and his or her family, and recognition of

  5. State of the art and the dark side of amyotrophic lateral sclerosis

    Institute of Scientific and Technical Information of China (English)

    Antonio; Musarò

    2010-01-01

    Amyotrophic lateral sclerosis(ALS) is a disorder that involves the degeneration of motor neurons,muscle atrophy,and paralysis.In a few familiar forms of ALS,mutations in the superoxide dismutase-1(SOD1) gene have been held responsible for the degeneration of motor neurons.Nevertheless,after the discovery of the SOD1 mutations no consensus has emerged as to which cells,tissues and pathways are primarily implicated in the pathogenic events that lead to ALS.Ubiquitous overexpression of mutant SOD1 in transgenic animals recapitulates the pathological features of ALS.However,the toxicity of mutant SOD1 is not necessarily limited to the central nervous system.Views about ALS pathogenesis are now enriched by the recent discovery of mutations in a pair of DNA/RNA-binding proteins called TDP-43 and FUS/TLS as causes of familial and sporadic forms of ALS.Although the steps that lead to the pathological state are well defined,several fundamental issues are still controversial:are the motor neurons the first direct targets of ALS;and what is the contribution of non-neuronal cells,if any,to the pathogenesis of ALS?The state of the art of ALS pathogenesis and the open questions are discussed in this review.

  6. The terminal latency of the phrenic nerve correlates with respiratory symptoms in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Park, Jin-Sung; Park, Donghwi

    2017-09-01

    The aim of the study was to investigate the electrophysiological parameters in phrenic nerve conduction studies (NCS) that sensitively reflect latent respiratory insufficiency present in amyotrophic lateral sclerosis (ALS). Forty-nine patients with ALS were examined, and after exclusion, 21 patients with ALS and their phrenic NCS results were reviewed. The patients were divided into two groups according to their respiratory sub-score in the ALS functional rating scale - revised (Group A, sub-score 12vs. Group B, sub-score 11). We compared the parameters of phrenic NCS between the two groups. There were no significant differences in the clinical characteristics between the two groups. Using a multivariate model, we found that the terminal latency of the phrenic nerve was the only parameter that was associated with early symptoms of respiratory insufficiency (pphrenic nerve was 7.65ms (sensitivity 80%, specificity 68.2%). The significantly prolonged terminal latency of the phrenic nerve in our study may reflect a profound distal motor axonal dysfunction of the phrenic nerve in patients with ALS in the early stage of respiratory insufficiency that can be used as a sensitive electrophysiological marker reflecting respiratory symptoms in ALS. The terminal latency of the phrenic nerve is useful for early detection of respiratory insufficiency in patients with ALS. Copyright © 2017. Published by Elsevier B.V.

  7. Is the effect of non-invasive ventilation on survival in amyotrophic lateral sclerosis age-dependent?

    OpenAIRE

    Siirala, Waltteri; Aantaa, Riku; Olkkola, Klaus T; Saaresranta, Tarja; Vuori, Arno

    2013-01-01

    Background Hypoventilation due to respiratory muscle atrophy is the most common cause of death as a result of amyotrophic lateral sclerosis (ALS). Patients aged over 65?years and presenting bulbar symptoms are likely to have a poorer prognosis. The aim of the study was to assess the possible impact of age and treatment with non-invasive ventilation (NIV) on survival in ALS. Based on evidence from earlier studies, it was hypothesized that NIV increases rates of survival regardless of age. Meth...

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

    Directory of Open Access Journals (Sweden)

    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.

  9. [The advance in the research and therapeutic trials of amyotrophic lateral sclerosis].

    Science.gov (United States)

    Moriwaka, F; Tashiro, K

    2000-12-01

    The research concerning with the pathogenesis of amyotrophic lateral sclerosis (ALS) has been in steady progress in the last 10 years, including discovery of SOD mutation in familial ALS. Riluzole, by its inhibiting excitatory amino acid release, is the only drug, which has been demonstrated the neuroprotective activity in the randomised double-blind placebo-controlled clinical trials in patients with ALS, although many other clinical therapeutic trials for ALS patients has been carried out. We discussed the clinical trials being the under way, especially SR57746A, (1-[2-(naphth-2-yl)ethy]-4-(3-trifluoromethyl phenyl)-1, 2, 5, 6-tetrahydro-pyridine, hydrochloride), a non-peptide compound which has been shown to exhibit a wide range of neurotrophic effects both in vitro and in vivo, and its phase II study in Japan and two kinds of phase III studies ongoing in the United States, Canada and Europe. We also introduced the clinical guideline for practice and care of ALS patients proposed by American Academy of Neurology, expecting to establish clinical guideline to be applicable to Japanese cases.

  10. The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine

    OpenAIRE

    Hedges, Erin C.; Mehler, Vera J.; Nishimura, Agnes L.

    2016-01-01

    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 ...

  11. Patient-derived olfactory mucosa for study of the non-neuronal contribution to amyotrophic lateral sclerosis pathology

    OpenAIRE

    García-Escudero, V.; Rosales, M.; Muñoz, J.L.; Scola, E.; Medina, J.; Khalique, H.; Garaulet, G.; Rodriguez, A.; Lim, F.

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease which currently has no cure. Research using rodent ALS models transgenic for mutant superoxide dismutase 1 (SOD1) has implicated that glial-neuronal interactions play a major role in the destruction of motor neurons, but the generality of this mechanism is not clear as SOD1 mutations only account for less than 2% of all ALS cases. Recently, this hypothesis was backed up by observation of similar effects using astrocyte...

  12. 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.

  13. [Differential diagnosis and atypical subsets of amyotrophic lateral sclerosis].

    Science.gov (United States)

    Pradat, P-F; Bruneteau, G

    2006-06-01

    Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of upper and lower motor neurons. In the absence of any validated biological marker, the diagnosis of ALS depends upon recognition of characteristic symptoms and signs together with supportive electrophysiological findings. The diagnosis of ALS is easy to recognize in its fully developed form but during the early stages both false positive and false negative diagnoses are common. In clinical practice, diagnostic difficulties mostly arise with patients who present either with only upper motor neuron, or with only lower motor neuron signs. It may be difficult to distinguish ALS with clinically predominant lower motor neuron involvement from alternative diagnoses including spinal atrophies of adult onset, Kennedy's disease, inclusion body myositis and motor neuropathies with conduction blocks. The diagnosis of ALS related syndromes (progressive muscular atrophy, primary lateral sclerosis and progressive bulbar palsy) requires the elimination of alternate diagnoses. This paper reviews the main characteristics of diseases mimicking ALS and the atypical subsets of ALS.

  14. Respiratory therapies for amyotrophic lateral sclerosis: a primer.

    Science.gov (United States)

    Gruis, Kirsten L; Lechtzin, Noah

    2012-09-01

    Respiratory complications are a common cause of morbidity and mortality in amyotrophic lateral sclerosis (ALS). Treatment of respiratory insufficiency with noninvasive ventilation (NIV) improves ALS patients' quality of life and survival. Evidence-based practice guidelines for the management of ALS patients recommend treatment of respiratory insufficiency with NIV as well as consideration of insufflation/exsufflation to improve clearance of airway secretions. Despite these recommendations respiratory therapies remain underused. In this review we provide a practical guide for the clinician to prescribe and manage respiratory therapies for the patient with ALS. Copyright © 2012 Wiley Periodicals, Inc.

  15. 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

  16. 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.

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Imaging the pathoanatomy of amyotrophic lateral sclerosis in vivo: targeting a propagation-based biological marker.

    Science.gov (United States)

    Kassubek, Jan; Müller, Hans-Peter; Del Tredici, Kelly; Lulé, Dorothée; Gorges, Martin; Braak, Heiko; Ludolph, Albert C

    2018-04-01

    Neuropathological studies in amyotrophic lateral sclerosis (ALS) have shown a dissemination in a regional sequence in four anatomically defined patterns. The aim of this retrospective study was to see whether longitudinal diffusion tensor imaging (DTI) data support the pathological findings. The application of DTI analysis to fibre structures that are prone to be involved at each neuropathological pattern of ALS was performed in a monocentre sample of 67 patients with ALS and 31 controls that obtained at least one follow-up scan after a median of 6 months. At the group level, longitudinal ALS data showed significant differences for the stage-related tract systems. At the individual level, 27% of the longitudinally scanned patients with ALS showed an increase in ALS stage, while the remaining were stable or were at the highest ALS stage. Longitudinal fractional anisotropy changes in the respective tract systems correlated significantly with the slope of the revised ALS functional rating scale. The DTI-based protocol was able to image the disease patterns of ALS in vivo cross-sectionally and longitudinally, in support of DTI as a technical marker to image ALS stages. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. 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

  20. Neuromuscular Junction Impairment in Amyotrophic Lateral Sclerosis: Reassessing the Role of Acetylcholinesterase.

    Science.gov (United States)

    Campanari, Maria-Letizia; García-Ayllón, María-Salud; Ciura, Sorana; Sáez-Valero, Javier; Kabashi, Edor

    2016-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a highly debilitating disease caused by progressive degeneration of motorneurons (MNs). Due to the wide variety of genes and mutations identified in ALS, a highly varied etiology could ultimately converge to produce similar clinical symptoms. A major hypothesis in ALS research is the "distal axonopathy" with pathological changes occurring at the neuromuscular junction (NMJ), at very early stages of the disease, prior to MNs degeneration and onset of clinical symptoms. The NMJ is a highly specialized cholinergic synapse, allowing signaling between muscle and nerve necessary for skeletal muscle function. This nerve-muscle contact is characterized by the clustering of the collagen-tailed form of acetylcholinesterase (ColQ-AChE), together with other components of the extracellular matrix (ECM) and specific key molecules in the NMJ formation. Interestingly, in addition to their cholinergic role AChE is thought to play several "non-classical" roles that do not require catalytic function, most prominent among these is the facilitation of neurite growth, NMJ formation and survival. In all this context, abnormalities of AChE content have been found in plasma of ALS patients, in which AChE changes may reflect the neuromuscular disruption. We review these findings and particularly the evidences of changes of AChE at neuromuscular synapse in the pre-symptomatic stages of ALS.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. The Use of Integrative Therapies in Patients with Amyotrophic Lateral Sclerosis in Shanghai, China

    Directory of Open Access Journals (Sweden)

    Weidong Pan

    2013-01-01

    Full Text Available Objective. To investigate the current use of integrative therapies (IT in the treatment of patients with amyotrophic lateral sclerosis (ALS. Methods. A cross-sectional, multicenter clinical epidemiological survey was conducted in 12 hospitals in Shanghai. We investigated the type and frequency of IT use and determined whether the use of IT correlated with demographic, social, or disease-specific characteristics in our patient population. Results. A total of 231 (89.5% of 258 patients with ALS were eligible for the study and 229 (99% of all of 231 reported the use of at least one IT for the treatment of ALS. Vitamins and Chinese herb decoctions, Chinese herb compounds, massage therapy, and acupuncture were the 5 most commonly used therapies. There was a strong association between education level, income, and use of IT. A household income of more than 75,000 RMB ($49,995 correlated with multiple IT use, and married patients used IT more often than single individuals. The main reasons for using IT were to treat weakness and fatigue, muscle atrophy, the development of ALS, depression, insomnia, limb pain or numbness, and side effects associated with Riluzole. Conclusion. The use of IT is common in patients with ALS in Shanghai. Vitamins and TCM are the most used additional therapies and the widespread and largely unexamined use of IT for ALS requires more attention.

  3. Lack of association between the APEX1 Asp148Glu polymorphism and sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Coppedè, Fabio; Lo Gerfo, Annalisa; Carlesi, Cecilia; Piazza, Selina; Mancuso, Michelangelo; Pasquali, Livia; Murri, Luigi; Migliore, Lucia; Siciliano, Gabriele

    2010-02-01

    Impairments in DNA repair enzymes have been observed in amyotrophic lateral sclerosis (ALS) tissues, particularly in the activity of the apurinic/apyrimidinic endonuclease 1 (APEX1). Moreover, it was suggested that the common APEX1 Asp148Glu polymorphism might be associated with ALS risk. To further address this question we performed the present study aimed at evaluating the contribution of the APEX1 Asp148Glu polymorphism in sporadic ALS (sALS) risk and clinical presentation, including age and site of onset and disease progression. We screened 134 sALS Italian patients and 129 matched controls for the presence of the APEX1 Asp148Glu polymorphism. No difference in APEX1 Asp148Glu allele and genotype frequencies was found between the groups, nor was the polymorphism associated with age and site of onset or disease progression. Present results do not support a role for the APEX1 Asp148Glu polymorphism in sALS pathogenesis in the Italian population.

  4. Elevated levels of ferritin in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.

    Science.gov (United States)

    Zheng, Y; Gao, L; Wang, D; Zang, D

    2017-08-01

    The aim of the study was to detect changes in the levels of ferritin heavy chain (FHC), ferritin light chain (FLC), and transferrin in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients and to analyze the correlations between the levels of these proteins and various clinical parameters. Cerebrospinal fluid and serum samples were obtained from 54 ALS patients and 46 non-inflammatory neurological disease control (non-INDC) patients. CSF and serum FHC, FLC, and transferring levels were measured via the enzyme-linked immunosorbent method using a commercial ELISA kit, and the times from onset (durations), ALS functional rating scale-revised (ALSFRS-r) scores, and disease progression rates (DPRs) were analyzed by registered neurologists. Statistical analysis was performed via Prism software. Compared with controls, ALS patients exhibited significantly increased FHC and FLC levels in CSF, which were positively correlated with DPR and negatively correlated with duration. Serum transferrin levels were significantly increased in ALS patients but were not correlated with disease progression. FHC and FLC in CSF rapidly increased as the disease worsened. This study demonstrated that the clinical measurement of FHC and FLC in CSF may be beneficial for disease differentiation and evaluating progression in patients with ALS. Compared with levels in serum, the levels of FHC and FLC in CSF might be more reliable for diagnosing and assessing the progression of ALS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Sawada, Hideyuki

    2017-05-01

    Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease. Although the pathogenesis remains unresolved, oxidative stress is known to play a pivotal role. Edaravone works in the central nervous system as a potent scavenger of oxygen radicals. In ALS mouse models, edaravone suppresses motor functional decline and nitration of tyrosine residues in the cerebrospinal fluid. Areas covered: Three clinical trials, one phase II open-label trial, and two phase III placebo-control randomized trials were reviewed. In all trials, the primary outcome measure was the changes in scores on the revised ALS functional rating scale (ALSFRS-R) to evaluate motor function of patients. Expert opinion: The phase II open label trial suggested that edaravone is safe and effective in ALS, markedly reducing 3-nitrotyrosine levels in the cerebrospinal fluid. One of the two randomized controlled trials showed beneficial effects in ALSFRS-R, although the differences were not significant. The last trial demonstrated that edaravone provided significant efficacy in ALSFRS-R scores over 24 weeks where concomitant use of riluzole was permitted. Eligibility was restricted to patients with a relatively short disease duration and preserved vital capacity. Therefore, combination therapy with edaravone and riluzole should be considered earlier.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Praline, Julien; Blasco, Hélène; Vourc'h, Patrick; Rat, Valérian; Gendrot, Chantal; Camu, William; Andres, Christian R

    2012-06-15

    Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Kabashi, Edor; Agar, Jeffrey N; Taylor, David M; Minotti, Sandra; Durham, Heather D

    2004-06-01

    Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene are responsible for a familial form of amyotrophic lateral sclerosis (fALS). The present study demonstrated impaired proteasomal function in the lumbar spinal cord of transgenic mice expressing human SOD-1 with the ALS-causing mutation G93A (SOD-1(G93A)) compared to non-transgenic littermates (LM) and SOD-1(WT) transgenic mice. Chymotrypsin-like activity was decreased as early as 45 days of age. By 75 days, chymotrypsin-, trypsin-, and caspase-like activities of the proteasome were impaired, at about 50% of control activity in lumbar spinal cord, but unchanged in thoracic spinal cord and liver. Both total and specific activities of the proteasome were reduced to a similar extent, indicating that a change in proteasome function, rather than a decrease in proteasome levels, had occurred. Similar decreases of total and specific activities of the proteasome were observed in NIH 3T3 cell lines expressing fALS mutants SOD-1(G93A) and SOD-1(G41S), but not in SOD-1(WT) controls. Although overall levels of proteasome were maintained in spinal cord of SOD-1(G93A) transgenic mice, the level of 20S proteasome was substantially reduced in lumbar spinal motor neurons relative to the surrounding neuropil. It is concluded that impairment of the proteasome is an early event and contributes to ALS pathogenesis.

  9. 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.

  10. Infectious agents and amyotrophic lateral sclerosis: another piece of the puzzle of motor neuron degeneration.

    Science.gov (United States)

    Castanedo-Vazquez, David; Bosque-Varela, Pilar; Sainz-Pelayo, Arancha; Riancho, Javier

    2018-05-29

    Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscle wasting and lacks an effective treatment. ALS pathogenesis has not been elucidated yet. In a small proportion of ALS patients, the disease has a familial origin, related to mutations in specific genes, which directly result in MN degeneration. By contrast, the vast majority of cases are though to be sporadic, in which genes and environment interact leading to disease in genetically predisposed individuals. Lately, the role of the environment has gained relevance in this field and an extensive list of environmental conditions have been postulated to be involved in ALS. Among them, infectious agents, particularly viruses, have been suggested to play an important role in the pathogenesis of the disease. These agents could act by interacting with some crucial pathways in MN degeneration, such as gene processing, oxidative stress or neuroinflammation. In this article, we will review the main studies about the involvement of microorganisms in ALS, subsequently discussing their potential pathogenic effect and integrating them as another piece in the puzzle of ALS pathogenesis.

  11. 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.

  12. 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. [Dept. of Neuroradiology, Hopital de la Timone, Marseille (France); Azulay, J.P.; Trefouret, S.; Pouget, J.; Serratrice, G. [Dept. of Neurology and Neuromuscular Diseases, Hopital de la Timone, Marseille (France); Viton, J.M. [Dept. of Physical Medicine and Rehabilitation, Hopital de la Timone, Marseille (France); Flori, A. [Medical Informatics Dept., Hopital Nord, Marseille (France)

    1999-10-01

    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.)

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

    International Nuclear Information System (INIS)

    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.)

  14. A muscle ultrasound score in the diagnosis of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Tsuji, Yukiko; Noto, Yu-Ichi; Shiga, Kensuke; Teramukai, Satoshi; Nakagawa, Masanori; Mizuno, Toshiki

    2017-06-01

    The aims of this study are to elucidate the frequencies and distribution of fasciculations using muscle ultrasound in patients with amyotrophic lateral sclerosis (ALS) and those with other conditions mimicking ALS, and subsequently to develop a novel fasciculation score for the diagnosis of ALS. Ultrasound of 21 muscles was performed to detect fasciculations in 36 consecutive patients suspected of having ALS. We developed a fasciculation ultrasound score that indicated the number of muscles with fasciculations in statistically selected muscles. A total of 525 muscles in 25 ALS patients and 231 in 11 non-ALS patients were analysed. Using relative operating characteristic and multivariate logistic regression analysis, we selected the trapezius, deltoid, biceps brachii, abductor pollicis brevis, abdominal, vastus lateralis, vastus medialis, biceps femoris, and gastrocnemius muscles for the fasciculation ultrasound score. The mean scores were higher in the ALS group than those in the non-ALS group (5.3±0.5vs. 0.3±0.7) (mean±SD); pdifferentiating ALS patients from non-ALS patients. The fasciculation ultrasound score can be a simple and useful diagnostic marker of ALS. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

  15. 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.

  16. Phosphoneurofilament heavy chain and N-glycomics from the cerebrospinal fluid in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Gonçalves, Margarida; Tillack, Linda; de Carvalho, Mamede; Pinto, Susana; Conradt, Harald S; Costa, Júlia

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron for which no clinically validated biomarkers have been identified. We have quantified by ELISA the biomarker phosphoneurofilament heavy chain (pNFH) in the cerebrospinal fluid (CSF) of ALS patients (n=29) and age-matched control patients with other diseases (n=19) by ELISA. Furthermore, we compared protein N-glycosylation of the CSF in ALS patients and controls, by applying a glycomics approach based on liquid chromatography and mass spectrometry. pNFH levels were significantly higher in ALS patients in comparison with controls (P<0.0001) in particular in fast progressors. The N-glycans found in the CSF were predominantly complex diantennary with sialic acid in α2,3- and α2,6-linkage, and bisecting N-acetylglucosamine-containing structures as well as peripherally fucosylated structures were found. As compared with controls the ALS group had a significant increase of a peak composed of the monosialylated diantennary glycans A2G2S(6)1 and FA2G2S(3)1 (P=0.0348). Our results underscore the value of pNFH as a biomarker in ALS. In addition, we identified a variation of the N-glycosylation pattern in ALS, suggesting that this change should be explored in future studies as potential biomarker. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Evaluation of the microbial diversity in amyotrophic lateral sclerosis using high-throughput sequencing

    Directory of Open Access Journals (Sweden)

    Xin Fang

    2016-09-01

    Full Text Available More and more evidences indicate that diseases of the central nervous system (CNS have been seriously affected by faecal microbes. However, little work is done to explore interaction between amyotrophic lateral sclerosis (ALS and faecal microbes. In the present study, high-throughput sequencing method was used to compare the intestinal microbial diversity of healthy people and ALS patients. The principal coordinate analysis (PCoA, Venn and unweighted pair-group method using arithmetic averages (UPGMA showed an obvious microbial changes between healthy people (group H and ALS patients (group A, and the average ratios of Bacteroides, Faecalibacterium, Anaerostipes, Prevotella, Escherichia and Lachnospira at genus level between ALS patients and healthy people were 0.78, 2.18, 3.41, 0.35, 0.79 and 13.07. Furthermore, the decreased Firmicutes/Bacteroidetes ratio at phylum level using LEfSE (LDA >4.0, together with the significant increased genus Dorea (harmful microorganisms and significant reduced genus Oscillibacter, Anaerostipes, Lachnospiraceae (beneficial microorganisms in ALS patients, indicated that the imbalance in intestinal microflora constitution had a strong association with the pathogenesis of ALS.

  18. Evaluation of the Microbial Diversity in Amyotrophic Lateral Sclerosis Using High-Throughput Sequencing.

    Science.gov (United States)

    Fang, Xin; Wang, Xin; Yang, Shaoguo; Meng, Fanjing; Wang, Xiaolei; Wei, Hua; Chen, Tingtao

    2016-01-01

    More and more evidences indicate that diseases of the central nervous system have been seriously affected by fecal microbes. However, little work is done to explore interaction between amyotrophic lateral sclerosis (ALS) and fecal microbes. In the present study, high-throughput sequencing method was used to compare the intestinal microbial diversity of healthy people and ALS patients. The principal coordinate analysis, Venn and unweighted pair-group method using arithmetic averages (UPGMA) showed an obvious microbial changes between healthy people (group H) and ALS patients (group A), and the average ratios of Bacteroides , Faecalibacterium , Anaerostipes , Prevotella , Escherichia , and Lachnospira at genus level between ALS patients and healthy people were 0.78, 2.18, 3.41, 0.35, 0.79, and 13.07. Furthermore, the decreased Firmicutes/Bacteroidetes ratio at phylum level using LEfSE (LDA > 4.0), together with the significant increased genus Dorea (harmful microorganisms) and significant reduced genus Oscillibacter , Anaerostipes , Lachnospiraceae (beneficial microorganisms) in ALS patients, indicated that the imbalance in intestinal microflora constitution had a strong association with the pathogenesis of ALS.

  19. The interaction of genetics and environmental toxicants in amyotrophic lateral sclerosis: results from animal models

    Institute of Scientific and Technical Information of China (English)

    Roger B. Sher

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in the progres-sive death of motor neurons, leading to paralysis and eventual death. There is presently no cure for ALS, and only two drugs are available, neither of which provide significant extension of life. The wide variation in onset and progression of the disease, both in sporadic and even in strongly penetrant monogenic famil-ial forms of ALS, indicate that in addition to background genetic variation impacting the disease process, environmental exposures are likely contributors. Epidemiological evidence worldwide implicates exposures to bacterial toxins, heavy metals, pesticides, and trauma as probable environmental factors. Here, we review current advances in gene-environment interactions in ALS animal models. We report our recent discov-eries in a zebrafish model of ALS in relation to exposure to the cyanobacterial toxin BMAA, and discuss several results from mouse models that show interactions with exposure to mercury and statin drugs, both leading to acceleration of the disease process. The increasing research into this combinatorial gene-environ-ment process is just starting, but shows early promise to uncover the underlying biochemical pathways that instigate the initial motor neuron defects and lead to their rapidly progressive dysfunction.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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.

  2. 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.

  3. 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.

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

    Science.gov (United States)

    Conti, Antonio; Riva, Nilo; Pesca, Mariasabina; Iannaccone, Sandro; Cannistraci, Carlo V; Corbo, Massimo; Previtali, Stefano C; Quattrini, Angelo; Alessio, Massimo

    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. All rights reserved.

  5. The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia.

    Science.gov (United States)

    Radford, Rowan A; Morsch, Marco; Rayner, Stephanie L; Cole, Nicholas J; Pountney, Dean L; Chung, Roger S

    2015-01-01

    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 conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies 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 summarize 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 characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future.

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

    Directory of Open Access Journals (Sweden)

    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. New ALS-Related Genes Expand the Spectrum Paradigm of Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Sabatelli, Mario; Marangi, Giuseppe; Conte, Amelia; Tasca, Giorgio; Zollino, Marcella; Lattante, Serena

    2016-03-01

    Amyotrophic Lateral Sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons. Clinical heterogeneity is a well-recognized feature of the disease as age of onset, site of onset and the duration of the disease can vary greatly among patients. A number of genes have been identified and associated to familial and sporadic forms of ALS but the majority of cases remains still unexplained. Recent breakthrough discoveries have demonstrated that clinical manifestations associated with ALS-related genes are not circumscribed to motor neurons involvement. In this view, ALS appears to be linked to different conditions over a continuum or spectrum in which overlapping phenotypes may be identified. In this review, we aim to examine the increasing number of spectra, including ALS/Frontotemporal Dementia and ALS/Myopathies spectra. Considering all these neurodegenerative disorders as different phenotypes of the same spectrum can help to identify common pathological pathways and consequently new therapeutic targets in these incurable diseases. © 2016 International Society of Neuropathology.

  8. Vascular endothelial growth factor and amyotrophic lateral sclerosis: the interplay with exercise and noninvasive ventilation.

    Science.gov (United States)

    Carilho, Rita; de Carvalho, Mamede; Swash, Michael; Pinto, Susana; Pinto, Anabela; Costa, Júlia

    2014-04-01

    We evaluated plasma vascular endothelial growth factor (VEGF) levels in patients with amyotrophic lateral sclerosis (ALS) with reference to the effects of respiratory failure, noninvasive ventilation (NIV), and exercise. We studied plasma VEGF levels in 83 ALS patients, 20 healthy controls, and 10 patients with other disorders. There were 4 groups of ALS patients: G1, 27 patients without respiratory problems; G2, 14 patients stabilized on nocturnal NIV; G3, 30 patients presenting with respiratory failure; G4, 12 patients on an aerobic exercise protocol. VEGF plasma levels did not differ significantly between ALS patients and controls, or between ALS groups. In G3, the mean VEGF levels increased 75% during NIV. In G4, the mean VEGF level increased by 300% during the exercise program. VEGF levels did not change during the course of the disease. VEGF levels in ALS depend on changes in ventilation and exercise but are probably not affected by the disease process itself. Copyright © 2013 Wiley Periodicals, Inc.

  9. Application of botulinum toxin to reduce the saliva in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Manrique, Dayse

    2005-01-01

    To demonstrate the effect of local application of Botox(R) in patients with amyotrophic lateral sclerosis (ALS), following our 2002 institutional protocol of sialorrhea treatment. Clinical prospective. Five patients with ALS assisted at Clinic of Otolaryngology of AACD (Associação de Assistência à Criança Deficiente). They were all submitted to local application of Botox in salivary glands and followed up for a year. The protocol consisted of clinical questionnaire about the inability of swallowing saliva and its repercussions in quality of life. Patients were submitted to previous odontological treatment, had intolerance to the adverse effects of anti-cholinergic agents and had not used Botox for at least six months. The application was guided by ultrasound and the doses were 30U in one point for submandibular gland, and 20U in two points for each parotid gland, after topic anesthetic with prilocaine. Five patients with ALS with sialorrhea, aged 45 to 59 years, were submitted to Botox salivary glands application. We observed that the symptoms of sialorrhea changed dramatically in four patients. Three patients stayed almost four months without complaints with repercussion in quality of life. No patient presented local or systemic effects with local injection of Botox.

  10. Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Riancho, J; Gonzalo, I; Ruiz-Soto, M; Berciano, J

    2016-02-04

    Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment. This article presents a review of ALS pathogenesis. To this end, we have reviewed published articles describing either ALS patients or ALS animal models and we discuss how the main cellular pathways (gene processing, protein metabolism, oxidative stress, axonal transport, relationship with neuronal microenvironment) may be involved in motor neurons degeneration. ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established. Copyright © 2016 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. A potential role for neuronal connexin 36 in the pathogenesis of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Belousov, Andrei B; Nishimune, Hiroshi; Denisova, Janna V; Fontes, Joseph D

    2018-02-14

    Neuronal gap junctional protein connexin 36 (Cx36) contributes to neuronal death following a range of acute brain insults such as ischemia, traumatic brain injury and epilepsy. Whether Cx36 contributes to neuronal death and pathological outcomes in chronic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), is not known. We show here that the expression of Cx36 is significantly decreased in lumbar segments of the spinal cord of both human ALS subjects and SOD1 G93A mice as compared to healthy human and wild-type mouse controls, respectively. In purified neuronal cultures prepared from the spinal cord of wild-type mice, knockdown of Cx36 reduces neuronal death caused by overexpression of the mutant human SOD1-G93A protein. Taken together, these data suggest a possible contribution of Cx36 to ALS pathogenesis. A perspective for the use of blockers of Cx36 gap junction channels for ALS therapy is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration.

    Science.gov (United States)

    Nagase, Midori; Yamamoto, Yorihiro; Miyazaki, Yusuke; Yoshino, Hiide

    2016-05-01

    Compared to age-matched healthy controls (n = 55), patients with amyotrophic lateral sclerosis (ALS) (n = 26) showed increased oxidative stress as indicated by a significantly increased percentage of oxidized coenzyme Q10 (%CoQ10) in total plasma coenzyme Q10, a significantly decreased level of plasma uric acid, and a significantly decreased percentage of polyunsaturated fatty acids in total plasma free fatty acids (FFA). Therefore, the efficacy of edaravone, a radical scavenger, in these ALS patients was examined. Among 26 ALS patients, 17 received edaravone (30 mg/day, one to four times a week) for at least 3 months, and 13 continued for 6 months. Changes in revised ALS functional rating scale (ALSFRS-R) were significantly smaller in these patients than in edaravone-untreated ALS patients (n = 19). Edaravone administration significantly reduced excursions of more than one standard deviation from the mean for plasma FFA levels and the contents of palmitoleic and oleic acids, plasma markers of tissue oxidative damage, in the satisfactory progress group (ΔALSFRS-R ≥ 0) as compared to the ingravescent group (ΔALSFRS-R Edaravone treatment increased plasma uric acid, suggesting that it is an effective scavenger of peroxynitrite. However, edaravone administration did not decrease %CoQ10. Therefore, combined treatment with agents such as coenzyme Q10 may further reduce oxidative stress in ALS patients.

  14. 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

  15. 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.

  16. The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Fukunaga, Kohji; Shinoda, Yasuharu; Tagashira, Hideaki

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) patients exhibit diverse pathologies such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction in motor neurons. Five to ten percent of patients have familial ALS, a form of the disease caused by mutations in ALS-related genes, while sporadic forms of the disease occur in 90-95% of patients. Recently, it was reported that familial ALS patients exhibit a missense mutation in SIGMAR1 (c.304G > C), which encodes sigma-1 receptor (Sig-1R), substituting glutamine for glutamic acid at amino acid residue 102 (p.E102Q). Expression of that mutant Sig-1R(E102Q) protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death in neuro2A cells. In this issue, we discuss mechanisms underlying mitochondrial impairment seen in ALS motor neurons and propose that therapies that protect mitochondria might improve the quality of life (QOL) of ALS patients and should be considered for clinical trials. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

  17. 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

  18. Chromogranin A levels in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Verde, Federico; Steinacker, Petra; Oeckl, Patrick; Weishaupt, Jochen H; Rosenbohm, Angela; Silani, Vincenzo; Ludolph, Albert C; Otto, Markus

    2018-07-01

    Chromogranin A (CgA) is a protein found in large dense-core vesicles of neuroendocrine cells and neurons and regulating secretion. A relevance to amyotrophic lateral sclerosis (ALS) was suggested as its overexpression accelerates disease onset in model systems and it interacts with mutant forms of SOD1. Recently, increased cerebrospinal fluid (CSF) CgA levels have been reported in ALS patients relative to controls. With the aim of confirming this finding, we measured CgA and phosphorylated neurofilament heavy chain (pNFH), an established ALS biomarker, in the CSF of 32 ALS patients and 32 disease controls. ALS patients had clearly increased pNFH levels (p < 0.0001), while CgA levels were only modestly lower relative to controls (p = 0.0265), with wide value overlap and consequently poor discriminative performance. CgA did not correlate with any disease parameters among ALS patients. Our findings suggest that CgA is not a promising clinical biomarker for ALS. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. 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.

  20. The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis.

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    Chen, Han-Jou; Mitchell, Jacqueline C; Novoselov, Sergey; Miller, Jack; Nishimura, Agnes L; Scotter, Emma L; Vance, Caroline A; Cheetham, Michael E; Shaw, Christopher E

    2016-05-01

    Detergent-resistant, ubiquitinated and hyperphosphorylated Tar DNA binding protein 43 (TDP-43, encoded by TARDBP) neuronal cytoplasmic inclusions are the pathological hallmark in ∼95% of amyotrophic lateral sclerosis and ∼60% of frontotemporal lobar degeneration cases. We sought to explore the role for the heat shock response in the clearance of insoluble TDP-43 in a cellular model of disease and to validate our findings in transgenic mice and human amyotrophic lateral sclerosis tissues. The heat shock response is a stress-responsive protective mechanism regulated by the transcription factor heat shock factor 1 (HSF1), which increases the expression of chaperones that refold damaged misfolded proteins or facilitate their degradation. Here we show that manipulation of the heat shock response by expression of dominant active HSF1 results in a dramatic reduction of insoluble and hyperphosphorylated TDP-43 that enhances cell survival, whereas expression of dominant negative HSF1 leads to enhanced TDP-43 aggregation and hyperphosphorylation. To determine which chaperones were mediating TDP-43 clearance we over-expressed a range of heat shock proteins (HSPs) and identified DNAJB2a (encoded by DNAJB2, and also known as HSJ1a) as a potent anti-aggregation chaperone for TDP-43. DNAJB2a has a J domain, allowing it to interact with HSP70, and ubiquitin interacting motifs, which enable it to engage the degradation of its client proteins. Using functionally deleted DNAJB2a constructs we demonstrated that TDP-43 clearance was J domain-dependent and was not affected by ubiquitin interacting motif deletion or proteasome inhibition. This indicates that TDP-43 is maintained in a soluble state by DNAJB2a, leaving the total levels of TDP-43 unchanged. Additionally, we have demonstrated that the levels of HSF1 and heat shock proteins are significantly reduced in affected neuronal tissues from a TDP-43 transgenic mouse model of amyotrophic lateral sclerosis and patients with

  1. Microstructural Correlates of Emotional Attribution Impairment in Non-Demented Patients with Amyotrophic Lateral Sclerosis.

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    Chiara Crespi

    Full Text Available Impairments in the ability to recognize and attribute emotional states to others have been described in amyotrophic lateral sclerosis patients and linked to the dysfunction of key nodes of the emotional empathy network. Microstructural correlates of such disorders are still unexplored. We investigated the white-matter substrates of emotional attribution deficits in a sample of amyotrophic lateral sclerosis patients without cognitive decline. Thirteen individuals with either probable or definite amyotrophic lateral sclerosis and 14 healthy controls were enrolled in a Diffusion Tensor Imaging study and administered the Story-based Empathy Task, assessing the ability to attribute mental states to others (i.e., Intention and Emotion attribution conditions. As already reported, a significant global reduction of empathic skills, mainly driven by a failure in Emotion Attribution condition, was found in amyotrophic lateral sclerosis patients compared to healthy subjects. The severity of this deficit was significantly correlated with fractional anisotropy along the forceps minor, genu of corpus callosum, right uncinate and inferior fronto-occipital fasciculi. The involvement of frontal commissural fiber tracts and right ventral associative fronto-limbic pathways is the microstructural hallmark of the impairment of high-order processing of socio-emotional stimuli in amyotrophic lateral sclerosis. These results support the notion of the neurofunctional and neuroanatomical continuum between amyotrophic lateral sclerosis and frontotemporal dementia.

  2. Microstructural Correlates of Emotional Attribution Impairment in Non-Demented Patients with Amyotrophic Lateral Sclerosis.

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    Crespi, Chiara; Cerami, Chiara; Dodich, Alessandra; Canessa, Nicola; Iannaccone, Sandro; Corbo, Massimo; Lunetta, Christian; Falini, Andrea; Cappa, Stefano F

    2016-01-01

    Impairments in the ability to recognize and attribute emotional states to others have been described in amyotrophic lateral sclerosis patients and linked to the dysfunction of key nodes of the emotional empathy network. Microstructural correlates of such disorders are still unexplored. We investigated the white-matter substrates of emotional attribution deficits in a sample of amyotrophic lateral sclerosis patients without cognitive decline. Thirteen individuals with either probable or definite amyotrophic lateral sclerosis and 14 healthy controls were enrolled in a Diffusion Tensor Imaging study and administered the Story-based Empathy Task, assessing the ability to attribute mental states to others (i.e., Intention and Emotion attribution conditions). As already reported, a significant global reduction of empathic skills, mainly driven by a failure in Emotion Attribution condition, was found in amyotrophic lateral sclerosis patients compared to healthy subjects. The severity of this deficit was significantly correlated with fractional anisotropy along the forceps minor, genu of corpus callosum, right uncinate and inferior fronto-occipital fasciculi. The involvement of frontal commissural fiber tracts and right ventral associative fronto-limbic pathways is the microstructural hallmark of the impairment of high-order processing of socio-emotional stimuli in amyotrophic lateral sclerosis. These results support the notion of the neurofunctional and neuroanatomical continuum between amyotrophic lateral sclerosis and frontotemporal dementia.

  3. Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis.

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    Liu, Kevin X; Edwards, Benjamin; Lee, Sheena; Finelli, Mattéa J; Davies, Ben; Davies, Kay E; Oliver, Peter L

    2015-05-01

    Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

  4. Case-control study of amyotrophic lateral sclerosis

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    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.

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

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    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.

  6. Clinical recognition and management of amyotrophic lateral sclerosis: the nurse's role.

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    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.

  7. 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.

  8. Evaluating the levels of interleukin-1 family cytokines in sporadic amyotrophic lateral sclerosis.

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    Italiani, Paola; Carlesi, Cecilia; Giungato, Paola; Puxeddu, Ilaria; Borroni, Barbara; Bossù, Paola; Migliorini, Paola; Siciliano, Gabriele; Boraschi, Diana

    2014-05-23

    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. 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. 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.

  9. Meta-analytic evaluation of the association between head injury and risk of amyotrophic lateral sclerosis.

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    Watanabe, Yukari; Watanabe, Takamitsu

    2017-10-01

    Head injury is considered as a potential risk factor for amyotrophic lateral sclerosis (ALS). However, several recent studies have suggested that head injury is not a cause, but a consequence of latent ALS. We aimed to evaluate such a possibility of reverse causation with meta-analyses considering time lags between the incidence of head injuries and the occurrence of ALS. We searched Medline and Web of Science for case-control, cross-sectional, or cohort studies that quantitatively investigated the head-injury-related risk of ALS and were published until 1 December 2016. After selecting appropriate publications based on PRISMA statement, we performed random-effects meta-analyses to calculate odds ratios (ORs) and 95% confidence intervals (CI). Sixteen of 825 studies fulfilled the eligibility criteria. The association between head injuries and ALS was statistically significant when the meta-analysis included all the 16 studies (OR 1.45, 95% CI 1.21-1.74). However, in the meta-analyses considering the time lags between the experience of head injuries and diagnosis of ALS, the association was weaker (OR 1.21, 95% CI 1.01-1.46, time lag ≥ 1 year) or not significant (e.g. OR 1.16, 95% CI 0.84-1.59, time lag ≥ 3 years). Although it did not deny associations between head injuries and ALS, the current study suggests a possibility that such a head-injury-oriented risk of ALS has been somewhat overestimated. For more accurate evaluation, it would be necessary to conduct more epidemiological studies that consider the time lags between the occurrence of head injuries and the diagnosis of ALS.

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

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    Carney, Sile; Corr, Bernie; Mays, Iain; Pender, Niall; Hardiman, Orla

    2018-01-01

    Objectives 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. Design In an open-ended question as part of a semistructured interview, caregivers were asked what would help them in their role. Interviews took place on three occasions at 4-month to 6-month intervals. Demographic, burden and quality of life data were collected, in addition to the open-ended responses. We carried out descriptive statistical analysis and thematic analysis of qualitative data. Setting and participants Home interviews at baseline (n=81) and on two further occasions (n=56, n=41) with informal caregivers of people with ALS attending the National ALS/MND Clinic at Beaumont Hospital, Dublin, Ireland. Results The majority of caregivers were family members. Hours of care provided and caregiver burden increased across the interview series. Thematic analysis identified what would help them in their role, and needs related to external support and services, psychological-emotional factors, patient-related behaviours, a cure and ‘nothing’. Themes were interconnected and their prevalence varied across the interview time points. Conclusion This study has shown the consistency and adaptation in what caregivers identified as helpful in their role, across 12–18 months of a caregiving journey. Support needs are clearly defined, and change with time and the course of caregiving. Caregivers need support from family, friends and healthcare professionals in managing their tasks and the emotional demands of caregiving. Identifying the specific needs of informal caregivers should enable health professionals to provide tailored supportive interventions

  11. The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis

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    David Benn Lovejoy

    2014-07-01

    Full Text Available Modulations of the potentially toxic transition metals iron (Fe and copper (Cu are implicated in the neurodegenerative process in a variety of human disease states including amyotrophic lateral sclerosis (ALS. However, the precise role played by these metals is still very much unclear, despite considerable clinical and experimental data suggestive of a role for these elements in the neurodegenerative process. The discovery of mutations in the antioxidant enzyme Cu/Zn superoxide dismutase (SOD-1 in ALS patients established the first known cause of ALS. Recent data suggest that various mutations in SOD-1 affect metal-binding of Cu and Zn, in turn promoting toxic protein aggregation. Copper homeostasis is also disturbed in ALS, and may be relevant to ALS pathogenesis. Another set of interesting observations in ALS patients involves the key nutrient Fe. In ALS patients Fe loading can be inferred by studies showing increased expression of serum ferritin, an Fe storage protein, with high serum ferritin levels correlating to poor prognosis. Magnetic resonance imaging of ALS patients shows a characteristic T2 shortening that is attributed to the presence of Fe in the motor cortex. In mutant SOD-1 mouse models, increased Fe is also detected in the spinal cord and treatment with Fe-chelating drugs lowers spinal cord Fe, preserves motor neurons and extends lifespan. Inflammation may play a key causative role in Fe accumulation, but this is not yet conclusive. Excess transition metals may enhance induction of endoplasmic reticulum (ER stress, a system that is already under strain in ALS. Taken together, the evidence suggests a role for transition metals in ALS progression and the potential use of metal-chelating drugs as a component of future ALS therapy.

  12. 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.

  13. Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis.

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    Kabashi, Edor; El Oussini, Hajer; Bercier, Valérie; Gros-Louis, François; Valdmanis, Paul N; McDearmid, Jonathan; Mejier, Inge A; Dion, Patrick A; Dupre, Nicolas; Hollinger, David; Sinniger, Jérome; Dirrig-Grosch, Sylvie; Camu, William; Meininger, Vincent; Loeffler, Jean-Philippe; René, Frédérique; Drapeau, Pierre; Rouleau, Guy A; Dupuis, Luc

    2013-06-15

    The mutations P56S and T46I in the gene encoding vesicle-associated membrane protein-associated protein B/C (VAPB) cause ALS8, a familial form of amyotrophic lateral sclerosis (ALS). Overexpression of mutant forms of VAPB leads to cytosolic aggregates, suggesting a gain of function of the mutant protein. However, recent work suggested that the loss of VAPB function could be the major mechanism leading to ALS8. Here, we used multiple genetic and experimental approaches to study whether VAPB loss of function might be sufficient to trigger motor neuron degeneration. In order to identify additional ALS-associated VAPB mutations, we screened the entire VAPB gene in a cohort of ALS patients and detected two mutations (A145V and S160Δ). To directly address the contribution of VAPB loss of function in ALS, we generated zebrafish and mouse models with either a decreased or a complete loss of Vapb expression. Vapb knockdown in zebrafish led to swimming deficits. Mice knocked-out for Vapb showed mild motor deficits after 18 months of age yet had innervated neuromuscular junctions (NMJs). Importantly, overexpression of VAPB mutations were unable to rescue the motor deficit caused by Vapb knockdown in zebrafish and failed to cause a toxic gain-of-function defect on their own. Thus, Vapb loss of function weakens the motor system of vertebrate animal models but is on its own unable to lead to a complete ALS phenotype. Our findings are consistent with the notion that VAPB mutations constitute a risk factor for motor neuron disease through a loss of VAPB function.

  14. Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients.

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    Martinez, Hector R; Gonzalez-Garza, Maria T; Moreno-Cuevas, Jorge E; Caro, Enrique; Gutierrez-Jimenez, Eugenio; Segura, Jose J

    2009-01-01

    Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons. CD133(+) stem cells are known to have the capacity to differentiate into neural lineages. Stem cells may provide an alternative treatment for ALS and other neurodegenerative diseases. Five men and five women (aged 38-62 years) with confirmed ALS were included in this study. Our institutional ethics and research committees approved the protocol. After informed consent was obtained, patients underwent Hidrogen-Magnetic Resonance Imaging (H-MRI) spectroscopy and were given scores according to an ALS functional rating scale, Medical Research Council power muscle scale and daily living activities. Bone marrow was stimulated with 300 microg filgrastim subcutaneously daily for 3 days. Peripheral blood mononuclear cells were obtained after admission by leukapheresis. The cell suspension was conjugated with anti-human CD133 superparamagnetic microbeads, and linked cells were isolated in a magnetic field. The isolated cells (2.5-7.5x10(5)) were resuspended in 300 microL of the patient's cerebrospinal fluid, and implanted in motor cortexes using a Hamilton syringe. Ten patients with confirmed ALS without transplantation were used as a control group. Patients were followed up for a period of 1 year. The autologous transplantation of CD133(+) stem cells into the frontal motor cortex is a safe and well-tolerated procedure in ALS patients. The survival of treated patients was statistically higher (P=0.01) than untreated control patients. Stem-cell transplantation in the motor cortex delays ALS progression and improves quality of life.

  15. Angiogenin induces modifications in the astrocyte secretome: relevance to amyotrophic lateral sclerosis.

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    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

  16. Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients

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    DeYoung Joseph

    2009-08-01

    Full Text Available Abstract Background Amyotrophic Lateral Sclerosis (ALS is a lethal disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Diagnosis is mainly based on clinical symptoms, and there is currently no therapy to stop the disease or slow its progression. Since access to spinal cord tissue is not possible at disease onset, we investigated changes in gene expression profiles in whole blood of ALS patients. Results Our transcriptional study showed dramatic changes in blood of ALS patients; 2,300 probes (9.4% showed significant differential expression in a discovery dataset consisting of 30 ALS patients and 30 healthy controls. Weighted gene co-expression network analysis (WGCNA was used to find disease-related networks (modules and disease related hub genes. Two large co-expression modules were found to be associated with ALS. Our findings were replicated in a second (30 patients and 30 controls and third dataset (63 patients and 63 controls, thereby demonstrating a highly significant and consistent association of two large co-expression modules with ALS disease status. Ingenuity Pathway Analysis of the ALS related module genes implicates enrichment of functional categories related to genetic disorders, neurodegeneration of the nervous system and inflammatory disease. The ALS related modules contain a number of candidate genes possibly involved in pathogenesis of ALS. Conclusion This first large-scale blood gene expression study in ALS observed distinct patterns between cases and controls which may provide opportunities for biomarker development as well as new insights into the molecular mechanisms of the disease.

  17. Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway.

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    Timothy G Lesnick

    2008-01-01

    Full Text Available We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs within axon guidance pathway genes were highly predictive of Parkinson disease (PD susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD.Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS; and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92x10(-60, survival free of ALS (hazards ratio = 149.80, p = 1.25x10(-74, and age at onset of ALS (R(2 = 0.86, p = 5.96x10(-66. We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively.Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.

  18. Laryngeal response patterns influence the efficacy of mechanical assisted cough in amyotrophic lateral sclerosis.

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    Andersen, Tiina; Sandnes, Astrid; Brekka, Anne Kristine; Hilland, Magnus; Clemm, Hege; Fondenes, Ove; Tysnes, Ole-Bjørn; Heimdal, John-Helge; Halvorsen, Thomas; Vollsæter, Maria; Røksund, Ola Drange

    2017-03-01

    Most patients with amyotrophic lateral sclerosis (ALS) are treated with mechanical insufflation-exsufflation (MI-E) in order to improve cough. This method often fails in ALS with bulbar involvement, allegedly due to upper-airway malfunction. We have studied this phenomenon in detail with laryngoscopy to unravel information that could lead to better treatment. We conducted a cross-sectional study of 20 patients with ALS and 20 healthy age-matched and sex-matched volunteers. We used video-recorded flexible transnasal fibre-optic laryngoscopy during MI-E undertaken according to a standardised protocol, applying pressures of ±20 to ±50 cm H 2 O. Laryngeal movements were assessed from video files. ALS type and characteristics of upper and lower motor neuron symptoms were determined. At the supraglottic level, all patients with ALS and bulbar symptoms (n=14) adducted their laryngeal structures during insufflation. At the glottic level, initial abduction followed by subsequent adduction was observed in all patients with ALS during insufflation and exsufflation. Hypopharyngeal constriction during exsufflation was observed in all subjects, most prominently in patients with ALS and bulbar symptoms. Healthy subjects and patients with ALS and no bulbar symptoms (n=6) coordinated their cough well during MI-E. Laryngoscopy during ongoing MI-E in patients with ALS and bulbar symptoms revealed laryngeal adduction especially during insufflation but also during exsufflation, thereby severely compromising the size of the laryngeal inlet in some patients. Individually customised settings can prevent this and thereby improve and extend the use of non-invasive MI-E. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  19. Amyotrophic lateral sclerosis with extension of the central canal of the spinal cord according to magnetic resonance imaging data

    OpenAIRE

    E. G. Mendelevich; G. R. Mukhamedzhanova; E. I. Bogdanov

    2016-01-01

    The paper describes an atypical case of amyotrophic lateral sclerosis (ALS) concurrent with extension of the central canal – hydromyelia.Diagnostic difficulty is due to the presence of symptoms which are atypical for ALS, such as early age of onset, slow progression with long-term involvement of one leg, as well as extension of the central canal of the spinal cord at the level of TIII-IX bodies, as evidenced by magnetic resonance imaging (MRI). The paper presents a clinical case, a review of ...

  20. Structural MRI correlates of amyotrophic lateral sclerosis progression.

    Science.gov (United States)

    Senda, Joe; Atsuta, Naoki; Watanabe, Hirohisa; Bagarinao, Epifanio; Imai, Kazunori; Yokoi, Daichi; Riku, Yuichi; Masuda, Michihito; Nakamura, Ryoichi; Watanabe, Hazuki; Ito, Mizuki; Katsuno, Masahisa; Naganawa, Shinji; Sobue, Gen

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) presents with varying degrees of brain degeneration that can extend beyond the corticospinal tract (CST). Furthermore, the clinical course and progression of ALS varies widely. Brain degeneration detected using structural MRI could reflect disease progression. On study registration, 3-Tesla volumetric MRI and diffusion tensor imaging scans were obtained at baseline in 38 healthy controls and 67 patients with sporadic ALS. Patients had Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores of ≥36 and did not have the chromosome 9, open reading frame 72 repeat expansion. Six months later, changes in ALSFRS-R (ΔALSFRS-R) scores were calculated and patients were grouped into three categories, namely, patients with slow progression with ΔALSFRS-R scores ≤3 (n=19), intermediate progression with ΔALSFRS-R scores =4, 5 and 6 (n=36) and rapid progression with ΔALSFRS-R scores ≥7 (n=12). We analysed voxel-based morphometry and tract-based spatial statistics among these subgroups and controls. In comparison with controls, patients with ALS showed grey matter atrophy and decreased fractional anisotropy beyond the motor cortex and CST, especially in the frontotemporal lobes and basal ganglia. Moreover, the degree of change was highly proportional to ΔALSFRS-R at the 6-month assessment. A more rapid disease progression and poorer functional decline were associated with greater involvement of the extra-motor cortex and basal ganglia, suggesting that the spatial extent of brain involvement can be an indicator of the progression in ALS. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  1. Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis.

    Science.gov (United States)

    Angelov, D N; Waibel, S; Guntinas-Lichius, O; Lenzen, M; Neiss, W F; Tomov, T L; Yoles, E; Kipnis, J; Schori, H; Reuter, A; Ludolph, A; Schwartz, M

    2003-04-15

    Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 +/- 7 days (n = 15) to 263 +/- 8 days (n = 14; P sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.

  2. Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Daoud, H; Valdmanis, P N; Kabashi, E; Dion, P; Dupré, N; Camu, W; Meininger, V; Rouleau, G A

    2009-02-01

    Mutations in the TARDBP gene, which encodes the TAR DNA binding protein (TDP-43), have been described in individuals with familial and sporadic amyotrophic lateral sclerosis (ALS). We screened the TARDBP gene in 285 French sporadic ALS patients to assess the frequency of TARDBP mutations in ALS. Six individuals had potentially deleterious mutations of which three were novel including a Y374X truncating mutation and P363A and A382P missense mutations. This suggests that TARDBP mutations may predispose to ALS in approximately 2% of the individuals followed in this study. Our findings, combined with those from other collections, brings the total number of mutations in unrelated ALS patients to 17, further suggesting that mutations in the TARDBP gene have an important role in the pathogenesis of ALS.

  3. Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis.

    Science.gov (United States)

    Carlesi, Cecilia; Pasquali, Livia; Piazza, Selina; Lo Gerfo, Annalisa; Caldarazzo Ienco, Elena; Alessi, Rosaria; Fornai, Francesco; Siciliano, Gabriele

    2011-03-01

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder of unknown aetiology that involves the loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Significant progress in understanding the cellular mechanisms of motor neuron degeneration in ALS has not been matched with the development of therapeutic strategies to prevent disease progression, and riluzole remains the only available therapy, with only marginal effects on disease survival. More recently alterations of mRNA processing in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations have provided important insights into the molecular networks implicated in the disease pathogenesis. Here we review some of the recent progress in promoting therapeutic strategies for neurodegeneration.

  4. Is erythropoietin gene a modifier factor in amyotrophic lateral sclerosis?

    Science.gov (United States)

    Ghezzi, Serena; Del Bo, Roberto; Scarlato, Marina; Nardini, Martina; Carlesi, Cecilia; Prelle, Alessandro; Corti, Stefania; Mancuso, Michelangelo; Briani, Chiara; Siciliano, Gabriele; Murri, Luigi; Bresolin, Nereo; Comi, Giacomo Pietro

    2009-05-01

    To investigate the role of erythropoietin (EPO) as genetic determinant in the susceptibility to sporadic amyotrophic lateral sclerosis (SALS). We sequenced a 259-bp region spanning the 3'hypoxia-responsive element of the EPO gene in 222 Italian SALS patients and 204 healthy subjects, matched for age and ethnic origin. No potentially causative variation was detected in SALS subjects; in addition, two polymorphic variants (namely C3434T and G3544T) showed the same genotype and haplotype frequencies in patients and controls. Conversely, a weak but significant association between G3544T and age of disease onset was observed (p=0.04). Overall, our data argue against the hypothesis of EPO as a genetic risk factor for motor neuron dysfunction, at least in Italian population. However, further studies on larger cohort of patients are needed to confirm the evidence of EPO gene as modifier factor.

  5. 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.

  6. 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.

  7. RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Mathis, Stéphane; Le Masson, Gwendal

    2018-01-15

    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.

  8. Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis

    NARCIS (Netherlands)

    Fogh, Isabella; Lin, Kuang; Tiloca, Cinzia; Rooney, James; Gellera, Cinzia; Diekstra, Frank P; Ratti, Antonia; Shatunov, Aleksey; van Es, Michael A; Proitsi, Petroula; Jones, Ashley; Sproviero, William; Chiò, Adriano; McLaughlin, Russell Lewis; Sorarù, Gianni; Corrado, Lucia; Stahl, Daniel; Del Bo, Roberto; Cereda, Cristina; Castellotti, Barbara; Glass, Jonathan D; Newhouse, Steven; Dobson, Richard; Smith, Bradley N; Topp, Simon; van Rheenen, Wouter; Meininger, Vincent; Melki, Judith; Morrison, Karen E; Shaw, Pamela J; Leigh, P Nigel; Andersen, Peter M; Comi, Giacomo P; Ticozzi, Nicola; Mazzini, Letizia; D'Alfonso, Sandra; Traynor, Bryan J; Van Damme, Philip; Robberecht, Wim; Brown, Robert H; Landers, John E; Hardiman, Orla; Lewis, Cathryn M; van den Berg, Leonard H; Shaw, Christopher E; Veldink, Jan H; Silani, Vincenzo; Al-Chalabi, Ammar; Powell, John

    Importance: Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. Objective: To identify gene variants

  9. Endogenous progesterone is associated to amyotrophic lateral sclerosis prognostic factors.

    Science.gov (United States)

    Gargiulo Monachelli, G; Meyer, M; Rodríguez, G E; Garay, L I; Sica, R E P; De Nicola, A F; González Deniselle, M C

    2011-01-01

    Negative prognostic factors in amyotrophic lateral sclerosis include advanced age, shorter time from disease onset to diagnosis, bulbar onset and rapid progression rate. To compare progesterone (PROG) and cortisol serum levels in patients and controls and ascertain its relationship to prognostic factors and survival. We assessed serum hormonal levels in 27 patients and 21 controls. Both hormones were 1.4-fold higher in patients. PROG showed a negative correlation with age, positive correlation with survival and positive trend with time to diagnosis. Increased PROG was observed in spinal onset and slow progression patients. No correlation was demonstrated with cortisol. Increased hormonal levels in patients are probably due to hypothalamic-pituitary-adrenal axis activation. Nevertheless, in this preliminary report only PROG correlated positively with factors predicting better prognosis and survival. We hypothesize endogenous PROG and cortisol may be engaged in differential roles, the former possibly involved in a neuroprotective response. © 2010 John Wiley & Sons A/S.

  10. 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)

  11. 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).

  12. CSF glial markers correlate with survival in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Süssmuth, S D; Sperfeld, A D; Hinz, A; Brettschneider, J; Endruhn, S; Ludolph, A C; Tumani, H

    2010-03-23

    In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), CSF biomarkers are increasingly studied to evaluate their relevance for differential diagnosis, disease progression, and understanding of pathophysiologic processes. To identify a biomarker profile of neuronal and glial CSF proteins to discriminate ALS from other motor neuron diseases (MND) and to assess whether baseline levels of CSF measures in ALS are associated with the course of the disease. A total of 122 consecutive subjects with MND were included in this cross-sectional study (ALS, n = 75; lower motor neuron syndrome, n = 39; upper motor neuron diseases, n = 8). Clinical follow-up included 76 patients. We determined baseline levels of protein tau and astroglial S100beta in CSF and microglial sCD14 in CSF and serum in relation to diagnosis, duration of disease, and survival. CSF tau was significantly elevated in ALS and upper motor neuron diseases as compared to lower motor neuron diseases and controls. CSF S100beta levels were significantly lower in lower motor neuron diseases as compared to other MND. CSF concentrations of S100beta and sCD14 correlated with the survival time in patients with ALS. In motor neuron diseases, CSF tau elevation indicates the degeneration of upper motor neurons, while S100 beta and sCD14 may indicate the activation of CNS glial cells. Because S100beta and sCD14 concentrations correlate with survival in amyotrophic lateral sclerosis (ALS), we suppose that the combination of both markers may be useful to obtain prognostic information in patients with ALS.

  13. Does the MUNIX Method Reflect Clinical Dysfunction in Amyotrophic Lateral Sclerosis: A Practical Experience.

    Science.gov (United States)

    Gawel, Malgorzata; Kuzma-Kozakiewicz, Magdalena

    2016-05-01

    The aim of our study was to assess the usefulness of the MUNIX method in reflecting the clinical dysfunction in patients with amyotrophic lateral sclerosis (ALS), as well as to assess an intra-rater reproducibility of MUNIX. The study group consisted of a total of 15 ALS patients. The mean age of symptoms onset was 55 years, and the mean disease duration was 10 months. The muscle strength and patients' functional status were assessed according to the Medical Research Council (MRC) and by ALS functional rating scale revised (ALSFRS-R), respectively. The MUNIX was performed in 6 muscles: abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), tibial anterior (TA), extensor digitorum brevis (EDB), and abductor hallucis (AH), unilaterally, at a less affected side. Both muscle-specific and global MRC and MUNIX scores were calculated. In 11 patients, the study protocol was repeated at least twice every 3 months. An additional testing of the intra-rater reliability was performed at the first visit.There were no significant differences between MUNIX test and re-test values in the APB, ADM, BB, TA, EDB, and AH muscles (P >0.05). The highest variability of the test-retest values was found in the BB muscle (7.53%). Although there was a significant test-retest difference in the global MUNIX score (P = 0.02), the variability of the results was as low as 1.26%. The MUNIX value correlated with the muscle-specific MRC score in ABP, ADM, TA, EDB and AH (P <0.05), and the global MUNIX values correlated with global MRC scores (P <0.05). There was also a significant correlation between the global MUNIX score and the clinical dysfunction measured by the ALSFRS-R scale (P <0.05). The global MUNIX showed a higher monthly decline (4.3%) as compared with ALFRS-R (0.7%) and the MRC global score (0.5%).This study confirms that the MUNIX method is a sensitive, reliable, and accurate tool reflecting both motor dysfunction and disease progression in ALS

  14. 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

  15. [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

  16. Effects of environmental enrichment on the amyotrophic lateral sclerosis mouse model.

    Science.gov (United States)

    Sorrells, A D; Corcoran-Gomez, K; Eckert, K A; Fahey, A G; Hoots, B L; Charleston, L B; Charleston, J S; Roberts, C R; Markowitz, H

    2009-04-01

    The manner in which an animal's environment is furnished may have significant implications for animal welfare as well as research outcomes. We evaluated four different housing conditions to determine the effects of what has been considered standard rodent enrichment and the exercise opportunities those environments allow on disease progression in the amyotrophic lateral sclerosis mouse model. Forty-eight copper/zinc superoxide dismutase mice (strain: B6SJL-TgN [SOD1-G931]1Gur) (SOD1) and 48 control (C) (strain: B6SJL-TgN[SOD1]2Gur) male mice were randomly assigned to four different conditions where 12 SOD1 and 12 C animals were allotted to each condition (n = 96). Conditions tested the effects of standard housing, a forced exercise regime, access to a mouse house and opportunity for ad libitum exercise on a running wheel. In addition to the daily all-occurrence behavioural sampling, mice were weighed and tested twice per week on gait and Rotor-Rod performance until the mice reached the age of 150 days (C) or met the criteria for our humane endpoint (SOD1). The SOD1 mice exposed to the forced exercise regime and wheel access did better in average lifespan and Rotor-Rod performance, than SOD1 mice exposed to the standard cage and mouse house conditions. In SOD1 mice, stride length remained longest throughout the progression of the disease in mice exposed to the forced exercise regime compared with other SOD1 conditions. Within the control group, mice in the standard cage and forced exercise regime conditions performed significantly less than the mice with the mouse house and wheels on the Rotor-Rod. Alpha motor neuron counts were highest in mice with wheels and in mice exposed to forced exercise regime in both mouse strains. All SOD1 mice had significantly lower alpha neuron counts than controls (P model, and may have implications for the effects of these strategies on experimental outcomes.

  17. Alterations in the Masticatory System in Patients with Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Riera-Punet, Nina; Martinez-Gomis, Jordi; Paipa, Andrés; Povedano, Monica; Peraire, Maria

    To determine the effect of amyotrophic lateral sclerosis (ALS) on aspects of masticatory function and to assess the relationship between ALS and the prevalence of traumatic mucosal lesions caused by oral self-injury. A total of 153 ALS patients and 23 control subjects participated in this cross-sectional study. Clinical characteristics including site of onset, medication, type of feeding, and use of noninvasive mechanical ventilation were recorded. The Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) protocol and a specific questionnaire to assess aspects of masticatory dysfunction and frequency of self-injury of the oral mucosa were applied to all participants. Maximum mandibular range of motion, maximum bite force, and maximum finger-thumb grip force were determined and tested with Mann Whitney, Kruskal-Wallis, or chi-square tests. P < .05 was considered significant. Maximum unassisted and assisted mouth opening, protrusion, left laterotrusion, and finger-thumb grip force were significantly reduced in both spinal- (n = 102) and bulbar-onset (n = 40) patients compared to the control group; however, bite force was reduced only in bulbar-onset patients. ALS patients with tube feeding (n = 16) had the greatest reduction in maximum bite force and mandibular opening. There was no relationship between TMD and ALS. Oral self-injury due to biting was more frequent in the ALS group (29.9%) than in the control group (8.7%) and in the bulbar-onset group (55.0%) compared to the spinal- (20.8%) and respiratory-onset (18.2%) groups. Of the ALS patients in the study, 10% sought dental treatment related to the condition. The ALS patients in this study had a reduction in finger-thumb grip force that was twice as great as the reduction in bite force. The maximum range of mandibular movement was also reduced, especially in bulbar-onset patients. ALS patients did not have a higher prevalence of TMD but did have more traumatic mucosal injury than controls. The dentist

  18. The predictive value of respiratory function tests for non-invasive ventilation in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Tilanus, T B M; Groothuis, J T; TenBroek-Pastoor, J M C; Feuth, T B; Heijdra, Y F; Slenders, J P L; Doorduin, J; Van Engelen, B G; Kampelmacher, M J; Raaphorst, J

    2017-07-25

    Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS) patients. The timing of referral to a home ventilation service (HVS), which is in part based on respiratory function tests, has shown room for improvement. It is currently unknown which respiratory function test predicts an appropriate timing of the initiation of NIV. We analysed, retrospectively, serial data of five respiratory function tests: forced vital capacity (FVC), peak cough flow (PCF), maximum inspiratory and expiratory pressure (MIP and MEP) and sniff nasal inspiratory pressure (SNIP) in patients with ALS. Patients who had had at least one assessment of respiratory function and one visit at the HVS, were included. Our aim was to detect the test with the highest predictive value for the need for elective NIV in the following 3 months. We analysed time curves, currently used cut-off values for referral, and respiratory function test results between 'NIV indication' and 'no-NIV indication' patients. One hundred ten patients with ALS were included of whom 87 received an NIV indication; 11.5% had one assessment before receiving an NIV indication, 88.5% had two or more assessments. The NIV indication was based on complaints of hypoventilation and/or proven (nocturnal) hypercapnia. The five respiratory function tests showed a descending trend during disease progression, where SNIP showed the greatest decline within the latest 3 months before NIV indication (mean = -22%). PCF at the time of referral to the HVS significantly discriminated between the groups 'NIV-indication' and 'no NIV-indication yet' patients at the first HVS visit: 259 (±92) vs. 348 (±137) L/min, p = 0.019. PCF and SNIP showed the best predictive characteristics in terms of sensitivity. SNIP showed the greatest decline prior to NIV indication and PCF significantly differentiated 'NIV-indication' from 'no NIV-indication yet' patients with ALS. Currently used cut-off values might be

  19. 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.

  20. What are the roles of carers in decision-making for amyotrophic lateral sclerosis multidisciplinary care?

    Directory of Open Access Journals (Sweden)

    Hogden A

    2013-02-01

    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, NSW, AustraliaPurpose: 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.Participants and methods: 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.Results: 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

  1. New insights into the gene expression associated to amyotrophic lateral sclerosis.

    Science.gov (United States)

    Recabarren-Leiva, Daniela; Alarcón, Marcelo

    2018-01-15

    Amyotrophic lateral sclerosis (ALS) is the most prevalent neuromuscular disease worldwide. It is a lethal and progressive neurodegenerative disease, principally affecting motor neurons; patient clinical characteristics are muscle weakness, dysphagia and respiratory failure. The mean age is related to family history (40years, familial ALS or FALS) or with no family history (50years), but it is more common in people aged 60-69years. The cause of ALS is not known and it is not known yet why it affects some people and not others. However expert consensus is that molecular alterations in different cells are involved in the development and progression of the disease. For example, motor neuron death is caused by a variety of cellular defects, including the processing of RNA molecules, water channels, and calcium levels, increasing evidence that these alterations of cells in the nervous system play an important role in ALS. Here we will systematically examine different genes (AQP1, SLC14A1, MT1X, DSCR1L1, PCP4, UCHL1, GABRA1, EGR1, OLFM1 and VSNL1) that are "up or down" regulated in the motor cortex and spinal cord and their association with ALS risk. These could be novel biomarkers associated with ALS risk. We built an interaction Network with Cytoscape, this was used to identify pathways, miRNA and drugs associated to ALS. The most important affected pathway is PI3K-Akt signaling. Thirteen microRNAs (miRNA-19B1, miRNA-107, miRNA-124-1, miRNA-124-2, miRNA-9-2, miRNA-29A, miRNA-9-3, miRNA-328, miRNA-19B2, miRNA-29B2, miRNA-124-3, miRNA-15A and miRNA-9-1) and four drugs (Estradiol, Acetaminophen, Progesterone and resveratrol) for new possible treatments were identified. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Implementation of a population-based epidemiological rare disease registry: study protocol of the amyotrophic lateral sclerosis (ALS - registry Swabia

    Directory of Open Access Journals (Sweden)

    Nagel Gabriele

    2013-02-01

    Full Text Available Abstract Background The social and medical impact of rare diseases is increasingly recognized. Amyotrophic lateral sclerosis (ALS is the most prevalent of the motor neuron diseases. It is characterized by rapidly progressive damage to the motor neurons with a survival of 2–5 years for the majority of patients. The objective of this work is to describe the study protocol and the implementation steps of the amyotrophic lateral sclerosis (ALS registry Swabia, located in the South of Germany. Methods/Design The ALS registry Swabia started in October 2010 with both, the retrospective (01.10.2008-30.09.2010 and prospective (from 01.10.2010 collection of ALS cases, in a target population of 8.6 million persons in Southern Germany. In addition, a population based case–control study was implemented based on the registry that also included the collection of various biological materials. Retrospectively, 420 patients (222 men and 198 women were identified. Prospectively data of ALS patients were collected, of which about 70% agreed to participate in the population-based case–control study. All participants in the case–control study provided also a blood sample. The prospective part of the study is ongoing. Discussion The ALS registry Swabia has been implemented successfully. In rare diseases such as ALS, the collaboration of registries, the comparison with external samples and biorepositories will facilitate to identify risk factors and to further explore the potential underlying pathophysiological mechanisms.

  3. The Åstrand-Ryhming Test is not a Feasible Measure in Ambulatory Patients with Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    van Groenestijn, Annerieke C; Verschuren, Olaf; Schröder, Carin D; van den Berg, Leonard H; Visser-Meily, Johanna M A

    2016-11-29

    Ambulatory patients with Amyotrophic Lateral Sclerosis (ALS) show a decreased aerobic capacity which may hamper the ability to perform activities of daily living. A standardized measure, however, for assessing aerobic capacity in patients with ALS during the disease course, is lacking. To examine the feasibility of the Åstrand-Ryhming (ÅR) test protocol longitudinally in ambulatory patients with amyotrophic lateral sclerosis (ALS). Seven ambulatory male patients with spinal ALS onset were assessed at baseline and at 4, 7 and 10 months' follow-up. Feasibility of the ÅR test protocol was analysed using percentage of: a) completed ÅR tests; b) achieved steady states; and c) predefined heart rates. Test completion decreased from 7/7 at baseline to 10/21 at follow-up due to ALS-related symptoms as fatigue, muscle weakness and cramps. Steady states and predefined heart rates were achieved in 12/17 and 17/17 of the completed tests, respectively. Overall, the feasibility of the ÅR test protocol declines from 5/7 at baseline to 7/21 at follow-up. The results suggest that changes in aerobic capacity in ambulatory patients with ALS could not be successfully monitored due to a diminished feasibility of the ÅR test protocol.

  4. Surgical improvement of speech disorder caused by amyotrophic lateral sclerosis.

    Science.gov (United States)

    Saigusa, Hideto; Yamaguchi, Satoshi; Nakamura, Tsuyoshi; Komachi, Taro; Kadosono, Osamu; Ito, Hiroyuki; Saigusa, Makoto; Niimi, Seiji

    2012-12-01

    Amyotrophic lateral sclerosis (ALS) is a progressive debilitating neurological disease. ALS disturbs the quality of life by affecting speech, swallowing and free mobility of the arms without affecting intellectual function. It is therefore of significance to improve intelligibility and quality of speech sounds, especially for ALS patients with slowly progressive courses. Currently, however, there is no effective or established approach to improve speech disorder caused by ALS. We investigated a surgical procedure to improve speech disorder for some patients with neuromuscular diseases with velopharyngeal closure incompetence. In this study, we performed the surgical procedure for two patients suffering from severe speech disorder caused by slowly progressing ALS. The patients suffered from speech disorder with hypernasality and imprecise and weak articulation during a 6-year course (patient 1) and a 3-year course (patient 2) of slowly progressing ALS. We narrowed bilateral lateral palatopharyngeal wall at velopharyngeal port, and performed this surgery under general anesthesia without muscle relaxant for the two patients. Postoperatively, intelligibility and quality of their speech sounds were greatly improved within one month without any speech therapy. The patients were also able to generate longer speech phrases after the surgery. Importantly, there was no serious complication during or after the surgery. In summary, we performed bilateral narrowing of lateral palatopharyngeal wall as a speech surgery for two patients suffering from severe speech disorder associated with ALS. With this technique, improved intelligibility and quality of speech can be maintained for longer duration for the patients with slowly progressing ALS.

  5. 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

    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......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...... stages of the cases' life cycle, different conclusions about where potential risk factors may exist might result....

  6. The severity of respiratory disorders in different forms of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    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

  7. Secular Trends of Amyotrophic Lateral Sclerosis: The Piemonte and Valle d'Aosta Register.

    Science.gov (United States)

    Chiò, Adriano; Mora, Gabriele; Moglia, Cristina; Manera, Umberto; Canosa, Antonio; Cammarosano, Stefania; Ilardi, Antonio; Bertuzzo, Davide; Bersano, Enrica; Cugnasco, Paolo; Grassano, Maurizio; Pisano, Fabrizio; Mazzini, Letizia; Calvo, Andrea

    2017-09-01

    This study reports the long-term epidemiologic trends of amyotrophic lateral sclerosis (ALS) based on a prospective register. To examine the 20-year epidemiologic trends of ALS in the Piemonte and Valle d'Aosta regions of Italy. The Piemonte and Valle d'Aosta Register for ALS (PARALS) is an epidemiologic prospective register that covers 2 Italian regions (population of 4 476 931 inhabitants according to the 2011 census) from January 1, 1995, through December 31, 2014. Case ascertainment is based on multiple sources (neurologic departments, hospital discharge archives, and mortality records). Incidence rates are age and sex standardized for the Italian population of the 2011 census. Age-period-cohort (APC) analysis was performed using a Poisson regression model. The primary study outcomes were long-term incidence and prevalence rates of ALS using a prospective design and their determinants. During the study period, a total of 2702 patients (mean [SD] age at onset, 65.7 [11.1] years; 1246 [46.1%] female and 1456 [53.9%] male) received a diagnosis of ALS between 1995 and 2014, corresponding to a crude annual incidence rate of 3.03 per 100 000 population (95% CI, 2.85-3.23) and an adjusted incidence rate of 2.78 per 100 000 population (95% CI, 2.57-2.96). The age-adjusted incidence rate increased in the 2 decades of the study (1995-2004: 2.66; 95% CI, 2.50-2.83; 2005-2014: 2.89; 95% CI, 2.71-3.07; P = .04), mostly in women. The adjusted rate ratio of men to women decreased from 1.27:1 (1995-2004) to 1.17:1 (2005-2014). The analysis of deviance for the APC regression models indicated that the drift variable is relevant in explaining the variation of ALS incidence rates over time in the overall population (change in deviance, 4.6553; P = .03) and in women (change in deviance, 3.8821; P = .05) but not in men (change in deviance, 0.77215; P = .38). A total of 479 patients with ALS were alive and had not undergone tracheostomy at the prevalence day

  8. 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

  9. Canine degenerative myelopathy: a model of human amyotrophic lateral sclerosis.

    Science.gov (United States)

    Nardone, Raffaele; Höller, Yvonne; Taylor, Alexandra C; Lochner, Piergiorgio; Tezzon, Frediano; Golaszewski, Stefan; Brigo, Francesco; Trinka, Eugen

    2016-02-01

    Canine degenerative myelopathy (CDM) represents a unique naturally occurring animal model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs, neuropathologic findings, and involvement of the superoxide dismutase 1 (SOD1) mutation. A definitive diagnosis can only be made postmortem through microscopic detection of axonal degeneration, demyelination and astroglial proliferation, which is more severe in the dorsal columns of the thoracic spinal cord and in the dorsal portion of the lateral funiculus. Interestingly, the muscle acetylcholine receptor complexes are intact in CDM prior to functional impairment, thus suggesting that muscle atrophy in CDM does not result from physical denervation. Moreover, since sensory involvement seems to play an important role in CDM progression, a more careful investigation of the sensory pathology in ALS is also warranted. The importance of SOD1 expression remains unclear, while oxidative stress and denatured ubiquinated proteins appear to play a crucial role in the pathogenesis of CDM. In this updated narrative review we performed a systematic search of the published studies on CDM that may shed light on the pathophysiological mechanisms of human ALS. A better understanding of the factors that determine the disease progression in CDM may be beneficial for the development of effective treatments for ALS. Copyright © 2015 Elsevier GmbH. All rights reserved.

  10. Amyotrophic lateral sclerosis with extension of the central canal of the spinal cord according to magnetic resonance imaging data

    Directory of Open Access Journals (Sweden)

    E. G. Mendelevich

    2016-01-01

    Full Text Available The paper describes an atypical case of amyotrophic lateral sclerosis (ALS concurrent with extension of the central canal – hydromyelia.Diagnostic difficulty is due to the presence of symptoms which are atypical for ALS, such as early age of onset, slow progression with long-term involvement of one leg, as well as extension of the central canal of the spinal cord at the level of TIII-IX bodies, as evidenced by magnetic resonance imaging (MRI. The paper presents a clinical case, a review of current literature on the clinical and MRI signs of ALS and on the differential diagnosis of motor neuron disease.

  11. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study

    NARCIS (Netherlands)

    E. Majounie (Elisa); A. Renton (Alan); K. Mok (Kin); E.G.P. Dopper (Elise); A. Waite (Adrian); S. Rollinson (Sara); A. Chiò (Adriano); G. Restagno (Gabriella); N. Nicolaou (Nayia); J. Simón-Sánchez (Javier); J.C. van Swieten (John); Y. Abramzon (Yevgeniya); J. Johnson (Janel); M. Sendtner (Michael); R. Pamphlett (Roger); R. Orrell (Richard); S. Mead (Simon); K.C. Sidle (Katie); H. Houlden (Henry); J.D. Rohrer (Jonathan Daniel); K.E. Morrison (Karen); H. Pall (Hardev); D. Talbot; O. Ansorge (Olaf); D.G. Hernandez (Dena); S. Arepalli (Sampath); M. Sabatelli (Mario); G. Mora (Gabriele); J.C. Corbo (Joseph); F. Giannini (Fabio); A. Calvo (Andrea); E. Englund (Elisabet); G. Borghero (Giuseppe); O.A.M. Floris; A. Remes (Anne); H. Laaksovirta (Hannu); L. McCluskey (Leo); J.Q. Trojanowski (John); V.M. Deerlin (Vivianna); G.D. Schellenberg (Gerard); M.A. Nalls (Michael); V.E. Drory (Vivian E); C.S. Lu (Chin-Song); T.-H. Yeh (Tu-Hsueh); H. Ishiura (Hiroyuki); Y. Takahashi (Yukari); S. Tsuji (Shoji); I. Le Ber (Isabelle); A. Brice; C. Drepper (Carsten); N. Williams (Nigel); J. Kirby (Janine); P.J. Shaw (Pamela); J. Hardy (John); P.J. Tienari (Pentti); P. Heutink (Peter); H. Morris (Huw); S. Pickering-Brown (Stuart); B.J. Traynor (Bryan)

    2012-01-01

    textabstractBackground: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods: We screened 4448 patients diagnosed with

  12. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

    NARCIS (Netherlands)

    Majounie, E.; Renton, A.E.; Mok, K.; Dopper, E.G.P.; Waite, A.; Rollinson, S.; Chio, A.; Restagno, G.; Nicolaou, N.; Simon-Sanchez, J.; van Swieten, J.C.; Abramzon, Y.; Johnson, J.O.; Sendtner, M.; Pamphlett, R.; Orrell, R.W.; Mead, S.; Sidle, K.C.; Houlden, H.; Rohrer, J.D.; Morrison, K.E.; Pall, H.; Talbot, K.; Ansorge, O.; Hernandez, D.G.; Arepalli, S.; Sabatelli, M.; Mora, G.; Corbo, M.; Giannini, F.; Calvo, A.; Englund, E.; Borghero, G.; Foris, G.L.; Remes, A.M.; Laaksovirta, H.; McCluskey, L.; Trojanowski, J.Q.; Van Deerlin, V.M.; Schellenberg, G.D.; Nalls, M.A.; Drory, V.E.; Lu, C.S.; Yeh, T.H.; Ishiura, H.; Takahashi, Y.; Tsuji, S.; Le Ber, I.; Brice, A.; Drepper, C.; Williams, N.; Kirby, J.; Shaw, P.; Hardy, J.; Tienari, P.J.; Heutink, P.; Morris, H.R.; Pickering-Brown, S.; Traynor, B.J.

    2012-01-01

    Background: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods: We screened 4448 patients diagnosed with ALS (El

  13. 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)

  14. The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine

    Directory of Open Access Journals (Sweden)

    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.

  15. The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine.

    Science.gov (United States)

    Hedges, Erin C; Mehler, Vera J; Nishimura, Agnes L

    2016-01-01

    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.

  16. Usefulness of diffusion tensor imaging in amyotrophic lateral sclerosis: potential biomarker and association with the cognitive profile

    Directory of Open Access Journals (Sweden)

    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.

  17. Screening of the transcriptional regulatory regions of vascular endothelial growth factor receptor 2 (VEGFR2 in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    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.

  18. The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy - a perspective on cell biological mechanisms.

    Science.gov (United States)

    Tang, Bor Luen

    2017-10-26

    Recent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.

  19. [Amyotrophic lateral sclerosis--when planning is almost too late].

    Science.gov (United States)

    Praxmarer, Veronika; Lahrmann, Heinz

    2006-05-01

    Amyotrophic lateral sclerosis (ALS) is a disease with progressive muscle weakness, also affecting respiratory muscles. In the terminal phase most patients experience a progression. Nutrition, speech and breathing capacity decrease. It is important to inform the patient and relatives in time and to give them a chance to decide. "Care Planning" and "Advance Directives" especially concerning ventilation reduces fear and helps the doctors and carers to decide, following the will of the patient. Nobody knows the speed of the progression. The patient in this case had few subjective symptoms at the time of the family conference. Progression till death lasted one month only. Treatment of his dyspnoe was not optimised, but during care all decisions were based on the actual will of the patient. Generally nocturnal hypoventilation, for instance non-invasive ventilation by BiPAP-mode, can relieve symptoms of dyspnoe in ALS patients. Low-dose morphine and/or benzodiazepine relieve respiratory discomfort and remove the negative spiral of dysnoe-fear-dyspnoe. Oxygen therapy is usually not needed (only in the very last stages of the disease) and is not recommended especially during the night. Hypercapnia can occur because of hypoventilation. This can cause growing unconsciousness and maybe death during sleep. Prolonging life is only possible by invasive long-term ventilation with all the problems of intensive care measures. The patient could have been given low dose morphine from the time of the family conference. Ventilation by CPAP-mode was insufficient for him.

  20. Evaluation of muscle MRI in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Baba, Yuri; Kuroiwa, Yoshiyuki

    2005-01-01

    Various objective measurements can be used to diagnose amyotrophic lateral sclerosis (ALS). T2-weighted brain MRI images revealed high signal areas at the posterior limb of the internal capsules in ALS patients. Recently, muscle MRI proved useful to evaluate abnormalities of the muscle in myositis patients. Therefore, in the present study, we examined muscle MRI of leg muscles in ALS patients, and correlated MRI with functional measurements, such as muscle strength, and compound muscle action potential amplitude of the tibialis anterior (TA) after stimulation of the peroneal nerve. The subjects consisted of 10 ALS patients (7 males and 3 females), ranging in age from 49 to 87. Neurologic symptoms at the onset of ALS consisted of bulbar dysfunction in one patient, upper extremity involvement in three patients, and lower extremity involvement in six patients. Muscle MRI of the legs was performed in 9 (ALS patients. A peripheral nerve conduction study was performed on the peroneal nerve, with the recording electrode over the TA. The T2-weighted muscle MRI images revealed high signal aeras in the muscle in six ALS patients, whose muscle weakness existed predominantly in the lower extremities. Extracellular fluid accumulation has been proposed to be responsible for the signal increase of denervated muscles on T2-weighted muscle MRI images. We assume that muscle MRI is useful to demonstrate the distribution of muscle involvement in ALS patients and to assess the disease's stage. (author)

  1. Respiratory insufficiency with preserved diaphragmatic function in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Yamauchi, Rika; Imai, Tomihiro; Tsuda, Emiko; Hozuki, Takayoshi; Yamamoto, Daisuke; Shimohama, Shun

    2014-01-01

    We performed a longitudinal study to elucidate the correlation between respiratory insufficiency and respiratory biomarkers, including diaphragmatic compound muscle action potential (DCMAP), at the initiation of noninvasive ventilation (NIV) in patients with amyotrophic lateral sclerosis (ALS). The patients were assessed at least every six months. Additional assessments were performed at the start of respiratory therapy when the patients met the criteria for the initiation of NIV. Each assessment consisted of a full neurological examination, a phrenic nerve conduction study, respiratory function tests, and nocturnal pulsed oximetry. We enrolled 43 patients with either definite or probable ALS as defined by the revised El Escorial criteria. The patients were divided into two groups according to the timing of the initiation of respiratory therapy. Seventeen patients (group A) met the criteria for NIV initiation when their DCMAP remained normal. Twenty-six patients (group B) met the criteria when their DCMAP decreased below normal limits. Although respiratory function parameters were significantly worse in group B compared with group A at NIV initiation, more than 80% of the patients in both groups developed nocturnal desaturation during sleep. DCMAP is not always a reliable indicator for determining the optimal timing for NIV initiation during the progression of respiratory insufficiency in ALS. Physicians should be aware of the risk of respiratory insufficiency during sleep in patients with ALS.

  2. Infrastructure resources for clinical research in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Sherman, Alexander V; Gubitz, Amelie K; Al-Chalabi, Ammar; Bedlack, Richard; Berry, James; Conwit, Robin; Harris, Brent T; Horton, D Kevin; Kaufmann, Petra; Leitner, Melanie L; Miller, Robert; Shefner, Jeremy; Vonsattel, Jean Paul; Mitsumoto, Hiroshi

    2013-05-01

    Clinical trial networks, shared clinical databases, and human biospecimen repositories are examples of infrastructure resources aimed at enhancing and expediting clinical and/or patient oriented research to uncover the etiology and pathogenesis of amyotrophic lateral sclerosis (ALS), a rapidly progressive neurodegenerative disease that leads to the paralysis of voluntary muscles. The current status of such infrastructure resources, as well as opportunities and impediments, were discussed at the second Tarrytown ALS meeting held in September 2011. The discussion focused on resources developed and maintained by ALS clinics and centers in North America and Europe, various clinical trial networks, U.S. government federal agencies including the National Institutes of Health (NIH), the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention (CDC), and several voluntary disease organizations that support ALS research activities. Key recommendations included 1) the establishment of shared databases among individual ALS clinics to enhance the coordination of resources and data analyses; 2) the expansion of quality-controlled human biospecimen banks; and 3) the adoption of uniform data standards, such as the recently developed Common Data Elements (CDEs) for ALS clinical research. The value of clinical trial networks such as the Northeast ALS (NEALS) Consortium and the Western ALS (WALS) Consortium was recognized, and strategies to further enhance and complement these networks and their research resources were discussed.

  3. Considerations for Clinical Neuropsychological Evaluation in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Woolley, Susan C; Rush, Beth K

    2017-11-01

    The clinical neuropsychologist has the opportunity to be uniquely involved in the evaluation and treatment of individuals with amyotrophic lateral sclerosis (ALS). We review the current literature that defines cognitive and behavioral symptoms in ALS, including current knowledge of the neuropathological and genetic underpinning for these symptoms. There are unique considerations for clinical neuropsychological evaluation and clinical research in ALS and we highlight these in this review. Specifically, we shed light on special factors that contribute to our understanding of cognitive and behavioral impairment in ALS, including co-morbid symptoms, differential diagnosis, and considerations for longitudinal tracking of phenotypes. We discuss the rationale for proposing a specific approach to such as cognitive screening, test selection, response modality consideration, and test-retest intervals. With this didactic overview, the clinical neuropsychologist has the potential to learn more about the heterogeneous presentation of motor and neuropsychological symptoms in ALS. Furthermore, the reader has the opportunity to understand what it takes to develop a valid assessment approach particularly when the phenotype of ALS remains undefined in some regards. This clinical practice review sets the stage for the clinical neuropsychologist to further contribute to our clinical and scientific understanding of ALS and cognition. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Intraspinal Stem Cell Transplantation for Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Chen, Kevin S.; Sakowski, Stacey A.; Feldman, Eva L.

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder in which the loss of upper and lower motor neurons produces progressive weakness and eventually death. In the decades since the approval of riluzole, the only FDA approved medication to moderately slow progression of ALS, no new therapeutics have arisen to alter the course of the disease. This is partly due to our incomplete understanding of the complex pathogenesis of motor neuron degeneration. Stem cells have emerged as an attractive option in treating ALS since they come armed with equally complex cellular machinery and may modulate the local microenvironment in many ways to rescue diseased motor neurons. While various stem cell types are being evaluated in preclinical and early clinical applications, here we review the preclinical strategies and advances supporting the recent clinical translation of neural progenitor cell therapy for ALS. Specifically, we focus on the use of spinal cord neural progenitor cells and the pipeline starting from preclinical studies to the designs of the Phase I and IIa clinical trials involving direct intraspinal transplantation in humans. PMID:26696091

  5. Association between macronutrient intake and amyotrophic lateral sclerosis prognosis.

    Science.gov (United States)

    Kim, Boeun; Jin, Youri; Kim, Seung Hyun; Park, Yongsoon

    2018-04-24

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, and the nutritional state of ALS patients is associated with survival. The purpose of the present study was to investigate whether macronutrient intake at early stage of the disease was positively associated with survival and duration from symptom onset to death, tracheostomy, or non-invasive ventilation (NIV) in ALS. ALS patients diagnosed according to EI Escorial criteria were recruited from 2011 to 2016 and followed up until 2017, when they reached the endpoint of death, tracheostomy, or NIV use. Dietary intake was estimated based on a 24-hour recall conducted less than 2 years from symptom onset, and the survival time was defined as the duration from symptom onset to the endpoint. ALS patients were categorized as short-term group (n=79) and long-term group (n=69) according to the mean survival time (33.03±14.01 months). Short-term survival was negatively associated with fat, protein, and meat intake, and positively associated with carbohydrate intake after adjustment for confounders. In addition, the survival time was positively associated with fat, protein, and meat intake but was not associated with carbohydrate intake. The present study suggested that higher intake of fat and protein, particularly from meat at early stage of the disease, could prolong the survival of ALS patients. However, further clinical trials are necessary to confirm the beneficial effects of higher fat and protein intake on mortality in ALS patients.

  6. Clinical care of patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Radunović, Aleksandar; Mitsumoto, Hiroshi; Leigh, P Nigel

    2007-10-01

    Although amyotrophic lateral sclerosis and its variants are readily recognised by neurologists, about 10% of patients are misdiagnosed, and delays in diagnosis are common. Prompt diagnosis, sensitive communication of the diagnosis, the involvement of the patient and their family, and a positive care plan are prerequisites for good clinical management. A multidisciplinary, palliative approach can prolong survival and maintain quality of life. Treatment with riluzole improves survival but has a marginal effect on the rate of functional deterioration, whereas non-invasive ventilation prolongs survival and improves or maintains quality of life. In this Review, we discuss the diagnosis, management, and how to cope with impaired function and end of life on the basis of our experience, the opinions of experts, existing guidelines, and clinical trials. We highlight the need for research on the effectiveness of gastrostomy, access to non-invasive ventilation and palliative care, communication between the care team, the patient and his or her family, and recognition of the clinical and social effects of cognitive impairment. We recommend that the plethora of evidence-based guidelines should be compiled into an internationally agreed guideline of best practice.

  7. Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Tibshirani, Michael; Zhao, Beibei; Gentil, Benoit J; Minotti, Sandra; Marques, Christine; Keith, Julia; Rogaeva, Ekaterina; Zinman, Lorne; Rouaux, Caroline; Robertson, Janice; Durham, Heather D

    2017-11-01

    Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS. © The Author 2017. Published by Oxford University Press. All rights reserved

  8. Analysis of dysarthria in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Watanabe, Sakae; Arasaki, Keisuke; Nagata, Hiroshi; Shouji, Shinichi.

    1994-01-01

    To evaluate dysarthria in patients with ALS, we used MRI (gradient rephasing echo method) and compared it with the computed acoustic analysis. Five ALS male patients of progressive bulbar palsy type and five normal males were asked to phonate the five Japanese vowels, /a/·/i/·/u/·/e/·/o/. MRI of the sagittal tongue and vocal tract was obtained by the gradient rephasing echo method (0.2 Tesla, TR: 30 ms, TE: 10 ms, FA: 25degC, Hitachi). We could clearly visualized the change of tongue shape and the narrow site of the vocal tract for each vowel phonation. In normal subjects, the tongue shape and the narrow site of the vocal tract were distinguishable between each vowel, but unclear in ALS. Acoustic analysis showed that the first formant frequency of /i/·/u/ in ALS was higher than normal and the second formant frequency of /i/·/e/ in ALS was significantly lower than normal. The discrepancy from the normal first, second and third formant frequency for each vowel of ALS was most seen in /i/·/ e/. It was speculated that /i/ and /e/ were the most disturbed vowels in ALS. The first and second formant frequency of vowel depends on the tongue shape and the width of the oral cavity. Therefore the results of the acoustic analysis in ALS indicated poor movement of tongue in /i/·/u/·/e/ and were compatible with the findings of the sagittal tongue MRI. The sagittal view of the tongue in the gradient rephasing echo MRI and the acoustic analysis are useful in evaluating dysarthria in ALS. (author)

  9. [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.

  10. Longitudinal course of cortical thickness decline in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Schuster, Christina; Kasper, Elisabeth; Machts, Judith; Bittner, Daniel; Kaufmann, Jörn; Benecke, Reiner; Teipel, Stefan; Vielhaber, Stefan; Prudlo, Johannes

    2014-10-01

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

  11. Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Mazzini, Letizia; Mareschi, Katia; Ferrero, Ivana; Vassallo, Elena; Oliveri, Giuseppe; Boccaletti, Riccardo; Testa, Lucia; Livigni, Sergio; Fagioli, Franca

    2006-07-01

    Our study was aimed to evaluate the feasibility and safety of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well-monitored amyotrophic lateral sclerosis (ALS) patients. Seven patients affected by definite ALS were enrolled in the study and two patients were treated for compassionate use and monitored for at least 3 years. Bone marrow was collected from the posterior iliac crest according to the standard procedure and MSCs were expanded ex vivo according to Pittenger's protocol. The cells were suspended in 2 ml autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector. The in vitro expanded MSCs did not show any bacterial o fungal contamination, hemopoietic cell contamination, chromosomic alterations and early cellular senescence. No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation and leg sensory dysesthesia, both reversible after a mean period of 6 weeks. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. A significant slowing down of the linear decline of the forced vital capacity was evident in four patients 36 months after MSCs transplantation. Our results demonstrate that direct injection of autologous expanded MSCs into the spinal cord of ALS patients is safe, with no significant acute or late toxicity, and well tolerated. The clinical results seem to be encouraging.

  12. 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.

  13. Management of patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Pautex, Sophie; Janssens, Jean-Paul; Vuagnat, Hubert; Conne, Pierre; Zulian, Gilbert B

    2005-10-15

    Standard recommendations for the clinical management of patient with ALS have been edited in recent years. These documents emphasise the importance of patient's autonomy. To measure how these different recommendations can be applied in the context of a general hospital without a specific ALS clinic. Review of medical records of 21 patients with an ALS diagnosis treated by the University Hospitals Geneva who died from 1996-2002. Patients suffered from distressing symptoms during their last hospitalisation. Artificial nutrition was given to 5 patients. Six patients had non invasive ventilation (NIV). Written advance directives were only available in 2 cases. Discussions about theses issues were also conducted late in the evolution of the disease. Some discrepancies between our daily practice and the existing recommendations exist, particularly regarding the key issues of artificial nutrition and ventilatory support.

  14. Current view and perspectives in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Stéphane Mathis

    2017-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS, identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease. Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS.

  15. Huntington's disease presenting as amyotrophic lateral sclerosis.

    LENUS (Irish Health Repository)

    Phukan, Julie

    2010-08-01

    We present the clinical, electrophysiological and molecular genetic findings of a 58-year-old male with genetically confirmed Huntington\\'s disease (HD) and concurrent clinically definite ALS by El Escorial criteria. The patient presented with asymmetric upper limb amyotrophy and weakness, and subsequently developed chorea and cognitive change. Genetic testing confirmed the presence of expanded trinucleotide repeats in huntingtin, consistent with a diagnosis of Huntington\\'s disease. This case confirms the rare coexistence of Huntington\\'s disease and motor neuron degeneration.

  16. 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.

  17. Cardiometabolic health and risk of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Timmins, Hannah C; Saw, Wilfred; Cheah, Benjamin C; Lin, Cindy S Y; Vucic, Steve; Ahmed, Rebekah M; Kiernan, Matthew C; Park, Susanna B

    2017-10-01

    Patients diagnosed with amyotrophic lateral sclerosis (ALS) generally have a limited medical history and a normal body mass index, raising the possibility of a premorbid ALS phenotype. The prevalence of cardiometabolic factors was analyzed in 58 ALS patients via comprehensive cardiovascular assessments and compared with Australian population norms. ALS patients had good cardiac fitness and no reported cardiovascular events. Average blood pressure, heart rate, PR interval, and corrected QT interval were in the normal range. There were significantly fewer obese women in the ALS cohort (13.6%, P < 0.05) and more men with a normal body mass index than in the general population (47.2%, P < 0.001). The percentage of individuals who had never smoked was greater for the ALS cohort (55.8%, P ≤ 0.001), and the prevalence of dyslipidemia was lower (38.7%) compared with the general population (74.4%, P < 0.001). ALS patients had good cardiometabolic health, with evidence of a reduced vascular risk profile. Muscle Nerve 56: 721-725, 2017. © 2016 Wiley Periodicals, Inc.

  18. Oximetry and indications for tracheotomy for amyotrophic lateral sclerosis.

    Science.gov (United States)

    Bach, John Robert; Bianchi, Carlo; Aufiero, Elaine

    2004-11-01

    To explore the use of oximetry as a guide for using respiratory aids and tracheotomy in the treatment of patients with amyotrophic lateral sclerosis (ALS). A retrospective review of all ALS patients presenting to a neuromuscular disease clinic since 1996. Patients who were symptomatic for nocturnal hypoventilation were prescribed noninvasive ventilation (NIV). Patients with assisted cough peak flows of NIV and MAC and the duration of normalization were recorded. When the baseline was not or could not be normalized, the time to acute respiratory failure and tracheotomy or death were recorded. Twenty-five patients became dependent on NIV, including 13 patients who received NIV continuously for a mean (+/- SD) period of 19.7 +/- 16.9 months, without desaturation (group 1). For another 76 patients, the daytime baseline Spo(2) level decreased to NIV/MAC (group 2) for a mean duration of 11.1 +/- 8.7 months before desaturation reoccurred for 27 patients. Of the latter patients, 11 underwent tracheotomy, 14 died in NIV or MAC. The long-term use of NIV and MAC, and the avoidance of tracheotomy is dependent on glottic function rather than on inspiratory or expiratory muscle failure.

  19. Impaired structural motor connectome in amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Esther Verstraete

    Full Text Available Amyotrophic lateral sclerosis (ALS is a severe neurodegenerative disease selectively affecting upper and lower motor neurons. Patients with ALS suffer from progressive paralysis and eventually die on average after three years. The underlying neurobiology of upper motor neuron degeneration and its effects on the complex network of the brain are, however, largely unknown. Here, we examined the effects of ALS on the structural brain network topology in 35 patients with ALS and 19 healthy controls. Using diffusion tensor imaging (DTI, the brain network was reconstructed for each individual participant. The connectivity of this reconstructed brain network was compared between patients and controls using complexity theory without--a priori selected--regions of interest. Patients with ALS showed an impaired sub-network of regions with reduced white matter connectivity (p = 0.0108, permutation testing. This impaired sub-network was strongly centered around primary motor regions (bilateral precentral gyrus and right paracentral lobule, including secondary motor regions (bilateral caudal middle frontal gyrus and pallidum as well as high-order hub regions (right posterior cingulate and precuneus. In addition, we found a significant reduction in overall efficiency (p = 0.0095 and clustering (p = 0.0415. From our findings, we conclude that upper motor neuron degeneration in ALS affects both primary motor connections as well as secondary motor connections, together composing an impaired sub-network. The degenerative process in ALS was found to be widespread, but interlinked and targeted to the motor connectome.

  20. Impaired structural motor connectome in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Verstraete, Esther; Veldink, Jan H; Mandl, Rene C W; van den Berg, Leonard H; van den Heuvel, Martijn P

    2011-01-01

    Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease selectively affecting upper and lower motor neurons. Patients with ALS suffer from progressive paralysis and eventually die on average after three years. The underlying neurobiology of upper motor neuron degeneration and its effects on the complex network of the brain are, however, largely unknown. Here, we examined the effects of ALS on the structural brain network topology in 35 patients with ALS and 19 healthy controls. Using diffusion tensor imaging (DTI), the brain network was reconstructed for each individual participant. The connectivity of this reconstructed brain network was compared between patients and controls using complexity theory without--a priori selected--regions of interest. Patients with ALS showed an impaired sub-network of regions with reduced white matter connectivity (p = 0.0108, permutation testing). This impaired sub-network was strongly centered around primary motor regions (bilateral precentral gyrus and right paracentral lobule), including secondary motor regions (bilateral caudal middle frontal gyrus and pallidum) as well as high-order hub regions (right posterior cingulate and precuneus). In addition, we found a significant reduction in overall efficiency (p = 0.0095) and clustering (p = 0.0415). From our findings, we conclude that upper motor neuron degeneration in ALS affects both primary motor connections as well as secondary motor connections, together composing an impaired sub-network. The degenerative process in ALS was found to be widespread, but interlinked and targeted to the motor connectome.

  1. 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.

  2. Non-invasive ventilation after surgery in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Olivieri, C; Castioni, C A; Livigni, S; Bersano, E; Cantello, R; Della Corte, F; Mazzini, L

    2014-04-01

    Surgery in patients affected by amyotrophic lateral sclerosis (ALS) presents a particular anesthetic challenge because of the risk of post-operative pulmonary complications. We report on the use of non-invasive ventilation (NIV) to prevent post-operative pulmonary complications (PPCs) in nine patients affected by ALS enrolled in a phase-1 clinical trial with stem cell transplantation. All patients were treated with autologous mesenchymal stem cells implanted into the spinal cord with a surgical procedure. Anesthesia was induced with propofol and maintained with remifentanil and sevoflurane. No muscle relaxant was used. After awakening and regain of spontaneous breathing, patients were tracheally extubated. Non-invasive ventilation through nasal mask was delivered and non-invasive positive pressure ventilation and continuous positive pressure ventilation were started. The average time on NIV after surgery was 3 h and 12 min. All patients regained stable spontaneous breathing after NIV discontinuation and had no episodes of respiratory failure until the following day. Our case series suggest that the use of NIV after surgery can be a safe strategy to prevent PPCs in patients affected by ALS. The perioperative procedure we chose for these patients appeared safe even in patients with advanced functional stage of the disease. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. 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.

  4. 25 years of neuroimaging in amyotrophic lateral sclerosis

    Science.gov (United States)

    Foerster, Bradley R.; Welsh, Robert C.; Feldman, Eva L.

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease for which a precise cause has not yet been identified. Standard CT or MRI evaluation does not demonstrate gross structural nervous system changes in ALS, so conventional neuroimaging techniques have provided little insight into the pathophysiology of this disease. Advanced neuroimaging techniques—such as structural MRI, diffusion tensor imaging and proton magnetic resonance spectroscopy—allow evaluation of alterations of the nervous system in ALS. These alterations include focal loss of grey and white matter and reductions in white matter tract integrity, as well as changes in neural networks and in the chemistry, metabolism and receptor distribution in the brain. Given their potential for investigation of both brain structure and function, advanced neuroimaging methods offer important opportunities to improve diagnosis, guide prognosis, and direct future treatment strategies in ALS. In this article, we review the contributions made by various advanced neuroimaging techniques to our understanding of the impact of ALS on different brain regions, and the potential role of such measures in biomarker development. PMID:23917850

  5. Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Gonzalez-Bermejo, Jesus; Morélot-Panzini, Capucine; Salachas, François; Redolfi, Stefania; Straus, Christian; Becquemin, Marie-Hélène; Arnulf, Isabelle; Pradat, Pierre-François; Bruneteau, Gaëlle; Ignagni, Anthony R; Diop, Moustapha; Onders, Raymond; Nelson, Teresa; Menegaux, Fabrice; Meininger, Vincent; Similowski, Thomas

    2012-01-01

    In amyotrophic lateral sclerosis (ALS) patients, respiratory insufficiency is a major burden. Diaphragm conditioning by electrical stimulation could interfere with lung function decline by promoting the development of type 1 muscle fibres. We describe an ancillary study to a prospective, non-randomized trial (NCT00420719) assessing the effects of diaphragm pacing on forced vital capacity (FVC). Sleep-related disturbances being early clues to diaphragmatic dysfunction, we postulated that they would provide a sensitive marker. Stimulators were implanted laparoscopically in the diaphragm close to the phrenic motor point in 18 ALS patients for daily conditioning. ALS functioning score (ALSFRS), FVC, sniff nasal inspiratory pressure (SNIP), and polysomnographic recordings (PSG, performed with the stimulator turned off) were assessed before implantation and after four months of conditioning (n = 14). Sleep efficiency improved (69 ± 15% to 75 ± 11%, p = 0.0394) with fewer arousals and micro-arousals. This occurred against a background of deterioration as ALSFRS-R, FVC, and SNIP declined. There was, however, no change in NIV status or the ALSFRS respiratory subscore, and the FVC decline was mostly due to impaired expiration. Supporting a better diaphragm function, apnoeas and hypopnoeas during REM sleep decreased. In conclusion, in these severe patients not expected to experience spontaneous improvements, diaphragm conditioning improved sleep and there were hints at diaphragm function changes.

  6. Factors predicting survival following noninvasive ventilation in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Peysson, S; Vandenberghe, N; Philit, F; Vial, C; Petitjean, T; Bouhour, F; Bayle, J Y; Broussolle, E

    2008-01-01

    The involvement of respiratory muscles is a major predicting factor for survival in amyotrophic lateral sclerosis (ALS). Recent studies show that noninvasive ventilation (NIV) can relieve symptoms of alveolar hypoventilation. However, factors predicting survival in ALS patients when treated with NIV need to be clarified. We conducted a retrospective study of 33 consecutive ALS patients receiving NIV. Ten patients had bulbar onset. We determined the median survivals from onset, diagnosis and initiation of NIV and factors predicting survival. Statistical analysis was performed using the Kaplan-Meier test and Cox proportional hazard models. The median initial and maximal total uses of NIV were 10 and 14 h/24h. The overall median survival from ALS onset was 34.2 months and worsened with increasing age and bulbar onset of the disease. The median survival from initiation of NIV was 8.4 months and was significantly poorer in patients with advanced age or with airway mucus accumulation. Survival from initiation of NIV was not influenced by respiratory parameters or bulbar symptoms. Advanced age at diagnosis and airway mucus accumulation represent poorer prognostic factors of ALS patients treated with NIV. NIV is a helpful treatment of sleep-disordered breathing, including patients with bulbar involvement. Copyright 2008 S. Karger AG, Basel.

  7. [Suspension of Respiratory Support in Patients with Amyotrophic Lateral Sclerosis].

    Science.gov (United States)

    Silberberg, Agustín A; Robetto, Josefina; Achával, Mora

    2018-01-01

    Decision making in advanced Amyotrophic Lateral Sclerosis (ALS) patients keeps on being a controversial issue. The aim of this work is to discuss ethical implications of withdrawing respiratory support treatment in patients with ALS. Through a bibliographic search on Pubmed database (2010-2016) we investigated whether or not the use of Non-Invasive Ventilation (NIV) and Mechanical Ventilation (MV) would increase survival and quality of life. We included 38 review articles. From these papers, results and ethical implications of initiating and mainly withdrawing respiratory support were analyzed. Survival time increased with NIV and with MV. Quality of life, above all according to physiological criteria, improved with NIV but regarding MV it remained controversial. Implementation and future withdrawal of MV seemed open to medical and ethical discussion. From a perspective of the intrinsic dignity of every human being, whatever its quality of life was, and knowing that no effective therapies for the underlying disease are available, the decision to remove MV in a patient with advanced ALS requires: knowledge of the will of the patient and, above all, evaluating whether this respiratory support measure is becoming objectively disproportionate.

  8. 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.

  9. 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.

  10. Widespread temporo-occipital lobe dysfunction in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Loewe, Kristian; Machts, Judith; Kaufmann, Jörn; Petri, Susanne; Heinze, Hans-Jochen; Borgelt, Christian; Harris, Joseph Allen; Vielhaber, Stefan; Schoenfeld, Mircea Ariel

    2017-01-09

    Recent studies suggest that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a single clinical continuum. However, previous neuroimaging studies have found only limited involvement of temporal lobe regions in ALS. To better delineate possible temporal lobe involvement in ALS, the present study aimed to examine changes in functional connectivity across the whole brain, particularly with regard to extra-motor regions, in a group of 64 non-demented ALS patients and 38 healthy controls. To assess between-group differences in connectivity, we computed edge-level statistics across subject-specific graphs derived from resting-state functional MRI data. In addition to expected ALS-related decreases in functional connectivity in motor-related areas, we observed extensive changes in connectivity across the temporo-occipital cortex. Although ALS patients with comorbid FTD were deliberately excluded from this study, the pattern of connectivity alterations closely resembles patterns of cerebral degeneration typically seen in FTD. This evidence for subclinical temporal dysfunction supports the idea of a common pathology in ALS and FTD.

  11. [Pyramidal syndrome in lateral amyotrophic sclerosis: clinico-morphological analysis].

    Science.gov (United States)

    Musaeva, L S; Zavalishin, I A; Gulevskaia, T S

    2003-01-01

    Retrospective clinical analysis with a special focus on pyramidal syndrome expression in the disease course as well as morphological study of brain and spinal structures in all levels of cortical-spinal projection (from brain motor cortex to spinal lumbar segments) have been conducted for 11 section cases of lateral amyotrophic sclerosis (LAS), sporadic type. Two groups of patients were studied: with pronounced pyramidal syndrome (spasticity, hyperreflexia, etc)--7 cases and with some signs of pyramidal deficiency (anisoreflexia, stability of peritoneal reflexes)--4 cases. Pyramidal syndrome in LAS is considered as an emergence of current neurodegenerative process, embracing a significant part of upper motor neurons of both precentral convolution and its axons along the whole length of cerebrospinal axis in the form of cytoplasmic inclusions and axonal spheroids. A presence of pathomorphological changes in other upper segmental structures of motor control reveals their role in pyramidal deficiency. Comparative analysis showed that expression of pyramidal syndrome signs and its correlation to atrophic paresis appearances is specifically determined by the severity of upper and lower motor neurons lesions. With regard to morphological changes in CNS structures, the peculiarities of some pyramidal syndrome appearances in LAS are analyzed.

  12. 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.

  13. Noninvasive ventilation reduces energy expenditure in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Georges, Marjolaine; Morélot-Panzini, Capucine; Similowski, Thomas; Gonzalez-Bermejo, Jesus

    2014-02-07

    Amyotrophic lateral sclerosis (ALS) leads to chronic respiratory failure. Diaphragmatic dysfunction, a major driver of dyspnea and mortality, is associated with a shift of the burden of ventilation to extradiaphragmatic inspiratory muscles, including neck muscles. Besides, energy expenditure is often abnormally high in ALS, and this is associated with a negative prognostic value. We hypothesized that noninvasive ventilation (NIV) would relieve inspiratory neck muscles and reduce resting energy expenditure (REE). Using indirect calorimetry, we measured REE during spontaneous breathing (REESB) and NIV (REENIV) in 16 ALS patients with diaphragmatic dysfunction, during the first 3 months of NIV. Measured values were compared with predicted REE (REEpred)(Harris-Benedict equation). NIV abolished inspiratory neck muscle activity. Even though our patients were not hypermetabolic, on the contrary, with a REESB that was lower than REEpred (average 11%), NIV did reduce energy expenditure. Indeed, median REENIV, in this population with a mean body mass index of 21.4 kg.m-2, was 1149 kcal/24 h [interquartile 970-1309], lower than REESB (1197 kcal/24 h, 1054-1402; mean difference 7%; p = 0.03, Wilcoxon). REESB and REENIV were correlated with forced vital capacity and maximal inspiratory pressure. NIV can reduce energy expenditure in ALS patients probably by alleviating the ventilatory burden imposed on inspiratory neck muscles to compensate diaphragm weakness. It remains to be elucidated whether or not, in which population, and to what extent, NIV can be beneficial in ALS through the corresponding reduction in energy expenditure.

  14. Impact of expiratory strength training in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Plowman, Emily K; Watts, Stephanie A; Tabor, Lauren; Robison, Raele; Gaziano, Joy; Domer, Amanda S; Richter, Joel; Vu, Tuan; Gooch, Clifton

    2016-06-01

    We evaluated the feasibility and impact of expiratory muscle strength training (EMST) on respiratory and bulbar function in persons with amyotrophic lateral sclerosis (ALS). Twenty-five ALS patients participated in this delayed intervention open-label clinical trial. Following a lead-in period, patients completed a 5-week EMST protocol. Outcome measures included: maximum expiratory pressure (MEP); physiologic measures of swallow and cough; and penetration-aspiration scale (PAS) scores. Of participants who entered the active phase of the study (n = 15), EMST was well tolerated and led to significant increases in MEPs and maximum hyoid displacement during swallowing post-EMST (P < 0.05). No significant differences were observed for PAS scores or cough spirometry measures. EMST was feasible and well tolerated in this small cohort of ALS patients and led to improvements in expiratory force-generating pressures and swallow kinematics. Further investigation is warranted to confirm these preliminary findings. Muscle Nerve 54: 48-53, 2016. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Guidelines in motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS) - from diagnosis to patient care.

    Science.gov (United States)

    Mitchell, J D

    2000-12-01

    This paper reviews the scope of current guidelines in motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS) and examines issues which have arisen in the preparation of these documents. The review concludes with an evaluation of the impact of the guidelines which have been produced to date and looks towards potential future developments in this area.

  17. Exposing asymmetric gray matter vulnerability in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Matthew S. Devine

    2015-01-01

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

  18. Exposing asymmetric gray matter vulnerability in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Devine, Matthew S; Pannek, Kerstin; Coulthard, Alan; McCombe, Pamela A; Rose, Stephen E; Henderson, Robert D

    2015-01-01

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

  19. 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…

  20. Mechanical cough augmentation techniques in amyotrophic lateral sclerosis/motor neuron disease

    OpenAIRE

    Rafiq, M.K.; Bradburn, M.; Mustfa, N.; Mcdermott, C.J.; Annane, D.

    2016-01-01

    © 2016 The Cochrane Collaboration.This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of mechanical insufflator/exsufflator (MI-E) and the breath-stacking technique for reducing morbidity and mortality and enhancing quality of life in people with amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).

  1. 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.

  2. 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 s...

  3. 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…

  4. Marital status is a prognostic factor in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Spataro, R; Volanti, P; Lo Coco, D; La Bella, V

    2017-12-01

    Several variables have been linked to a shorter survival in patients with amyotrophic lateral sclerosis (ALS), for example, female sex, older age, site of disease onset, rapid disease progression, and a relatively short diagnostic delay. With regard to marital status, previous studies suggested that living with a partner might be associated to a longer survival and a higher likelihood to proceed to tracheostomy. Therefore, to further strengthen this hypothesis, we investigated the role of marital status as a prognostic variable in a cohort of ALS patients. We performed a retrospective analysis on 501 consecutive ALS patients for which a complete disease's natural history and clinical/demographic data were available. At diagnosis, 409 patients (81.6%) were married or lived with a stable partner, whereas 92 patients (18.4%) were single/widowed/divorced. In our ALS cohort, being married was associated with a median longer survival (married, 35 months [24-50] vs unmarried, 27 months [18-42]; Pmarried and unmarried patients were significantly different in many clinical and demographic variables, including age at disease onset, gender, body mass index, and number of children. Cox regression analysis showed that age at onset, diagnostic delay, and marital status were independent predictors of survival. In unmarried patients, female sex was also significantly associated with shorter survival. Marital status is a prognostic factor in ALS, and it significantly affects survival. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. 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; Baas, Frank; ten Asbroek, Anneloor L. M. A.

    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

  6. Involvement of corpus callosum in amyotrophic lateral sclerosis shown by MRI

    Energy Technology Data Exchange (ETDEWEB)

    Zandijcke, M. van [Dept. of Neurology, Bruges (Belgium); Casselman, J. [Dept. of Medical Imaging, Bruges (Belgium)

    1995-05-01

    Abnormal high signal in the corticospinal tracts on MRI has been described in amyotrophic lateral sclerosis. We report a case with further high signal in fibres of the corpus callosum on proton density and T2-weighted spin-echo images, closely matching findings of earlier pathological reports. (orig.)

  7. Involvement of corpus callosum in amyotrophic lateral sclerosis shown by MRI

    International Nuclear Information System (INIS)

    Zandijcke, M. van; Casselman, J.

    1995-01-01

    Abnormal high signal in the corticospinal tracts on MRI has been described in amyotrophic lateral sclerosis. We report a case with further high signal in fibres of the corpus callosum on proton density and T2-weighted spin-echo images, closely matching findings of earlier pathological reports. (orig.)

  8. Is chronic ventilatory support really effective in patients with amyotrophic lateral sclerosis?

    NARCIS (Netherlands)

    Hazenberg, A.; Kerstjens, H. A. M.; Prins, S. C. L.; Vermeulen, K. M.; Wijkstra, P. J.

    2016-01-01

    Most patients with amyotrophic lateral sclerosis (ALS) develop respiratory insufficiency in the advanced stage of their disease. Non-invasive ventilation (NIV) is commonly regarded to be a treatment that is effective in reducing these complaints. To assess whether the effect of NIV on gas exchange

  9. Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Gaastra, Benjamin; Shatunov, Aleksey; Pulit, Sara; Jones, Ashley R; Sproviero, William; Gillett, Alexandra; Chen, Zhongbo; Kirby, Janine; Fogh, Isabella; Powell, John F; Leigh, P Nigel; Morrison, Karen E; Shaw, Pamela J; Shaw, Christopher E; van den Berg, Leonard H; Veldink, Jan H; Lewis, Cathryn M; Al-Chalabi, Ammar

    2016-01-01

    Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA

  10. Physical activity and risk of Amyotrophic Lateral Sclerosis in a prospective cohort study

    NARCIS (Netherlands)

    Gallo, Valentina; Vanacore, Nicola; Bueno-de-Mesquita, H. Bas; Vermeulen, Roel; Brayne, Carol; Pearce, Neil; Wark, Petra A.; Ward, Heather A.; Ferrari, Pietro; Jenab, Mazda; Andersen, Peter M.; Wennberg, Patrik; Wareham, Nicholas; Katzke, Verena; Kaaks, Rudolf; Weiderpass, Elisabete; Peeters, Petra H.; Mattiello, Amalia; Pala, Valeria; Barricante, Aurelio; Chirlaque, Maria Dolores; Travier, Noémie; Travis, Ruth C.; Sanchez, Maria Jose; Pessah-Rasmussen, Hélène; Petersson, Jesper; Tjønneland, Anne; Tumino, Rosario; Quiros, Jose Ramon; Trichopoulou, Antonia; Kyrozis, Andreas; Oikonomidou, Despoina; Masala, Giovanna; Sacerdote, Carlotta; Arriola, Larraitz; Boeing, Heiner; Vigl, Matthaeus; Claver-Chapelon, Francoise; Middleton, Lefkos; Riboli, Elio; Vineis, Paolo

    2016-01-01

    Previous case–control studies have suggested a possible increased risk of Amyotrophic Lateral Sclerosis (ALS) with physical activity (PA), but this association has never been studied in prospective cohort studies. We therefore assessed the association between PA and risk of death from ALS in the

  11. Physical activity and risk of Amyotrophic Lateral Sclerosis in a prospective cohort study

    NARCIS (Netherlands)

    Gallo, Valentina; Vanacore, Nicola; Bueno-de-Mesquita, H Bas; Vermeulen, Roel; Brayne, Carol; Pearce, Neil; Wark, Petra A; Ward, Heather A; Ferrari, Pietro; Jenab, Mazda; Andersen, Peter M; Wennberg, Patrik; Wareham, Nicholas; Katzke, Verena; Kaaks, Rudolf; Weiderpass, Elisabete; Peeters, Petra H; Mattiello, Amalia; Pala, Valeria; Barricante, Aurelio; Chirlaque, Maria-Dolores; Travier, Noémie; Travis, Ruth C; Sanchez, Maria-Jose; Pessah-Rasmussen, Hélène; Petersson, Jesper; Tjønneland, Anne; Tumino, Rosario; Quiros, Jose Ramon; Trichopoulou, Antonia; Kyrozis, Andreas; Oikonomidou, Despoina; Masala, Giovanna; Sacerdote, Carlotta; Arriola, Larraitz; Boeing, Heiner; Vigl, Matthaeus; Claver-Chapelon, Francoise; Middleton, Lefkos; Riboli, Elio; Vineis, Paolo

    Previous case-control studies have suggested a possible increased risk of Amyotrophic Lateral Sclerosis (ALS) with physical activity (PA), but this association has never been studied in prospective cohort studies. We therefore assessed the association between PA and risk of death from ALS in the

  12. 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

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

    NARCIS (Netherlands)

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

  14. 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.

    Background and purposeThirty 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

  15. 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

  16. 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;

  17. Euthanasia and physician-assisted suicide in amyotrophic lateral sclerosis: a prospective study

    NARCIS (Netherlands)

    Maessen, M.; Veldink, J.H.; Onwuteaka-Philipsen, B.D.; Hendricks, H.T.; Schelhaas, H.J.; Grupstra, H.F.; van der Wal, G.; Van den Berg, L.H.

    2014-01-01

    The objective of this study is to determine if quality of care, symptoms of depression, disease characteristics and quality of life of patients with amyotrophic lateral sclerosis (ALS) are related to requesting euthanasia or physician-assisted suicide (EAS) and dying due to EAS. Therefore, 102 ALS

  18. 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...

  19. Genotype-Property Patient-Phenotype Relations Suggest that Proteome Exhaustion Can Cause Amyotrophic Lateral Sclerosis

    DEFF Research Database (Denmark)

    Kepp, Kasper Planeta

    2015-01-01

    Late-onset neurodegenerative diseases remain poorly understood as search continues for the perceived pathogenic protein species. Previously, variants in Superoxide Dismutase 1 (SOD1) causing Amyotrophic Lateral Sclerosis (ALS) were found to destabilize and reduce net charge, suggesting a pathogen...

  20. Lingual-Alveolar Contact Pressure during Speech in Amyotrophic Lateral Sclerosis: Preliminary Findings

    Science.gov (United States)

    Searl, Jeff; Knollhoff, Stephanie; Barohn, Richard J.

    2017-01-01

    Purpose: This preliminary study on lingual-alveolar contact pressures (LACP) in people with amyotrophic lateral sclerosis (ALS) had several aims: (a) to evaluate whether the protocol induced fatigue, (b) to compare LACP during speech (LACP-Sp) and during maximum isometric pressing (LACP-Max) in people with ALS (PALS) versus healthy controls, (c)…

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

    Science.gov (United States)

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

    2018-01-26

    The aim of this study was to gain insight into experiences and reflections of persons with amyotrophic lateral sclerosis and relatives concerning the peer group rehabilitation programme "More Life - Less Illness". This qualitative study used the Interpretive Description methodology with Symbolic Interactionism as the analytical framework. Eighteen programme participants representing persons with amyotrophic lateral sclerosis (n = 8) and relatives (n = 10) were included. Data consisted of individual interviews and participant observation. The analysis revealed two categorical themes, "Sense of Community Building" and "Understanding my ALS", which represented the participants' experiences and reflections on peer group rehabilitation. Through the analysis, it became apparent that "Sense of Community Building" gave rise to an increased and personalised understanding of amyotrophic lateral sclerosis among the participants. As a part of the continuous processing of the knowledge gained, "Facing Facts" and "Retaining Normality" appeared as subthemes regarding the participants' ability to live a less dependent and more meaningful life. This study of peer group rehabilitation for persons with amyotrophic lateral sclerosis and relatives indicates that programme participation leads to positive experiences in terms of living a shared meaningful life despite severe disability. The findings may guide practice to develop longitudinal peer group rehabilitation programmes 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 sessions enables a continuous processing of shared experiences and gained knowledge. Joint participation of persons with amyotrophic lateral sclerosis and their relatives supports both their internal

  2. MRI and clinical features in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Waragai, M.

    1997-01-01

    MRI of the brain and spinal cord was performed in 21 patients with amyotrophic lateral sclerosis (ALS), 8 normal volunteers and 16 neurological disease controls. High signal was seen in the intracranial corticospinal tract in 16 of the 21 patients on T2-weighted and in 10 on proton density (PD)-weighted images. In one patient, the high signal on T2-weighted images became less marked with progression of the disease. Low signal intensity was seen in the motor cortex in 12 of the 21 patients. High signal in the anterolateral column of the spinal cord on T1 weighted images was seen in 14, and high signal in the lateral corticospinal tract on T2 weighted images was seen in 7 of the 21 patients. The relationship between the abnormal images and upper motor neurone signs remained unclear. High signal intensity was seen in the corticospinal tract in the brain on T2-weighted images in two normal volunteers and four disease controls, and on PD weighted images in three disease controls.Low signal intensity in the motor cortex on T2 weighted images was seen in three normal volunteers and four disease controls. However, high signal intensity was seen in the intracranial corticospinal tract on T1 weighted images in five patients with ALS who showed pronounced upper motor neurone signs including spastic paraparesis, but not in controls. Thus, abnormalities on MRI in the brain and spinal cord should be considered in the diagnosis of ALS, and high signal intensity of the intracranial corticospinal tract on T1-weighted images may reflect the severe pathological changes of the upper motor neurones in ALS. (orig.)

  3. MRI and clinical features in amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Waragai, M. [Department of Neurology, Chiba University (Japan)

    1997-12-01

    MRI of the brain and spinal cord was performed in 21 patients with amyotrophic lateral sclerosis (ALS), 8 normal volunteers and 16 neurological disease controls. High signal was seen in the intracranial corticospinal tract in 16 of the 21 patients on T2-weighted and in 10 on proton density (PD)-weighted images. In one patient, the high signal on T2-weighted images became less marked with progression of the disease. Low signal intensity was seen in the motor cortex in 12 of the 21 patients. High signal in the anterolateral column of the spinal cord on T1 weighted images was seen in 14, and high signal in the lateral corticospinal tract on T2 weighted images was seen in 7 of the 21 patients. The relationship between the abnormal images and upper motor neurone signs remained unclear. High signal intensity was seen in the corticospinal tract in the brain on T2-weighted images in two normal volunteers and four disease controls, and on PD weighted images in three disease controls.Low signal intensity in the motor cortex on T2 weighted images was seen in three normal volunteers and four disease controls. However, high signal intensity was seen in the intracranial corticospinal tract on T1 weighted images in five patients with ALS who showed pronounced upper motor neurone signs including spastic paraparesis, but not in controls. Thus, abnormalities on MRI in the brain and spinal cord should be considered in the diagnosis of ALS, and high signal intensity of the intracranial corticospinal tract on T1-weighted images may reflect the severe pathological changes of the upper motor neurones in ALS. (orig.) With 3 figs., 1 tab., 19 refs.

  4. Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Douaud, Gwenaëlle; Filippini, Nicola; Knight, Steven; Talbot, Kevin; Turner, Martin R

    2011-12-01

    Amyotrophic lateral sclerosis as a system failure is a concept supported by the finding of consistent extramotor as well as motor cerebral pathology. The functional correlates of the structural changes detected using advanced magnetic resonance imaging techniques such as diffusion tensor imaging and voxel-based morphometry have not been extensively studied. A group of 25 patients with amyotrophic lateral sclerosis was compared to healthy control subjects using a multi-modal neuroimaging approach comprising T(1)-weighted, diffusion-weighted and resting-state functional magnetic resonance imaging. Using probabilistic tractography, a grey matter connection network was defined based upon the prominent corticospinal tract and corpus callosum involvement demonstrated by white matter tract-based spatial statistics. This 'amyotrophic lateral sclerosis-specific' network included motor, premotor and supplementary motor cortices, pars opercularis and motor-related thalamic nuclei. A novel analysis protocol, using this disease-specific grey matter network as an input for a dual-regression analysis, was then used to assess changes in functional connectivity directly associated with this network. A spatial pattern of increased functional connectivity spanning sensorimotor, premotor, prefrontal and thalamic regions was found. A composite of structural and functional magnetic resonance imaging measures also allowed the qualitative discrimination of patients from controls. An integrated structural and functional connectivity approach therefore identified apparently dichotomous processes characterizing the amyotrophic lateral sclerosis cerebral network failure, in which there was increased functional connectivity within regions of decreased structural connectivity. Patients with slower rates of disease progression showed connectivity measures with values closer to healthy controls, raising the possibility that functional connectivity increases might not simply represent a

  5. 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.

  6. Severe brain atrophy after long-term survival seen in siblings with familial amyotrophic lateral sclerosis and a mutation in the optineurin gene: a case series.

    Science.gov (United States)

    Ueno, Hiroki; Kobatake, Keitaro; Matsumoto, Masayasu; Morino, Hiroyuki; Maruyama, Hirofumi; Kawakami, Hideshi

    2011-12-12

    Previous studies have shown widespread multisystem degeneration in patients with sporadic amyotrophic lateral sclerosis who develop a total locked-in state and survive under mechanical ventilation for a prolonged period of time. However, the disease progressions reported in these studies were several years after disease onset. There have been no reports of long-term follow-up with brain imaging of patients with familial amyotrophic lateral sclerosis at an advanced stage of the disease. We report the cases of siblings with amyotrophic lateral sclerosis with homozygous deletions of the exon 5 mutation of the gene encoding optineurin, in whom brain computed tomography scans were followed up for more than 20 years. The patients were a Japanese brother and sister. The elder sister was 33 years of age at the onset of disease, which began with muscle weakness of her left lower limb. Two years later she required mechanical ventilation. She became bedridden at the age of 34, and died at the age of 57. A computed tomography scan of her brain at the age of 36 revealed no abnormality. Atrophy of her brain gradually progressed. Ten years after the onset of mechanical ventilation, atrophy of her whole brain, including the cerebral cortex, brain stem and cerebellum, markedly progressed. Her younger brother was 36 years of age at the onset of disease, which presented as muscle weakness of his left upper limb. One year later, he showed dysphagia and dysarthria, and tracheostomy ventilation was performed. He became bedridden at the age of 37 and died at the age of 55. There were no abnormal intracranial findings on brain computed tomography scans obtained at the age of 37 years. At the age of 48 years, computed tomography scans showed marked brain atrophy with ventricular dilatation. Subsequently, atrophy of the whole brain rapidly progressed as in his elder sister. We conclude that a homozygous deletion-type mutation in the optineurin gene may be associated with widespread

  7. The use of subcutaneous glycopyrrolate in the management of sialorrhoea and facilitating the use of non-invasive ventilation in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Cooper-Knock, Johnathan; Ahmedzai, Sam H; Shaw, Pamela

    2011-11-01

    Sialorrhoea is a recognized complication of bulbar amyotrophic lateral sclerosis (ALS) that leads to an increased risk of potentially harmful aspiration and often prevents patients from tolerating non-invasive ventilation (NIV). A case of treatment-resistant sialorrhoea in bulbar ALS is described where subcutaneous glycopyrrolate was effective without significant side-effects. The patient went on to markedly increase the length of time she could tolerate NIV each night.

  8. The possible meaning of fractional anisotropy measurement of the cervical spinal cord in correct diagnosis of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Budrewicz, Slawomir; Szewczyk, Pawel; Bladowska, Joanna; Podemski, Ryszard; Koziorowska-Gawron, Ewa; Ejma, Maria; Słotwiński, Krzysztof; Koszewicz, Magdalena

    2016-03-01

    Diagnosis of amyotrophic lateral sclerosis (ALS) is based on clinical criteria and electrophysiological tests (electromyography, and transcranial magnetic stimulation). In the search for ALS biomarkers, the role of imaging procedures is currently emphasized, especially modern MR techniques. MR procedures were performed on 15 ALS patients and a sex- and age-matched control group. The MR examinations were performed with a 1.5-T MR unit, and the protocol consisted of sagittal T1-weighed images, sagittal and axial T2-weighed images, and sagittal T2-weighed FAT SAT images followed by an axial diffusion tensor imaging (DTI) sequence of the cervical spinal cord. FA values in individual segments of the cervical spinal cord were decreased in the ALS group in comparison with the control group. After comparing FA values for anterior, posterior, and lateral corticospinal columns, the greatest difference was observed between the C2 and C5 segments. Spinal cord assessment with the use of FA measurements allows for confirmation of the motor pathways lesion in ALS patients. The method, together with clinical criteria, could be helpful in ALS diagnosis, assessment of clinical course, or even the effects of new drugs. The results also confirmed the theory of the generalized character of ALS.

  9. 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 (p<0.001) were significantly more recommended in PD than in ALS. Compensatory and sensorial maneuvers are more recommended to rehabilitee program in both diseases. 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.

  10. Death with dignity in Washington patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Wang, Leo H; Elliott, Michael A; Jung Henson, Lily; Gerena-Maldonado, Elba; Strom, Susan; Downing, Sharon; Vetrovs, Jennifer; Kayihan, Paige; Paul, Piper; Kennedy, Kate; Benditt, Joshua O; Weiss, Michael D

    2016-11-15

    To describe the amyotrophic lateral sclerosis (ALS) patients who sought medication under the Washington State Death with Dignity (DWD) Act since its inception in 2009. Chart review at 3 tertiary medical centers in the Seattle/Puget Sound region and comparison to publicly available data of ALS and all-cause DWD cohorts from Washington and Oregon. In Washington State, 39 patients with ALS requested DWD from the University of Washington, Virginia Mason, and Swedish Medical Centers beginning in 2009. The median age at death was 65 years (range 46-86). Seventy-seven percent of the patients used the prescriptions. All of the patients who used the medications passed away without complications. The major reasons for patients to request DWD as reported by participating physicians were loss of autonomy and dignity and decrease in enjoyable activities. Inadequate pain control, financial cost, and loss of bodily control were less commonly indicated. These findings were similar to those of the 92 patients who sought DWD in Oregon. In Washington and Oregon, the percentage of patients with ALS seeking DWD is higher compared to the cancer DWD cohort. Furthermore, compared to the all-cause DWD cohort, patients with ALS are more likely to be non-Hispanic white, married, educated, enrolled in hospice, and to have died at home. Although a small number, ALS represents the disease with the highest proportion of patients seeking to participate in DWD. Patients with ALS who choose DWD are well-educated and have access to palliative or life-prolonging care. The use of the medications appears to be able to achieve the patients' goals without complications. © 2016 American Academy of Neurology.

  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. Cortical thinning and clinical heterogeneity in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Mezzapesa, Domenico Maria; D'Errico, Eustachio; Tortelli, Rosanna; Distaso, Eugenio; Cortese, Rosa; Tursi, Marianna; Federico, Francesco; Zoccolella, Stefano; Logroscino, Giancarlo; Dicuonzo, Franca; Simone, Isabella Laura

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) has heterogeneous clinical features that could be translated into specific patterns of brain atrophy. In the current study we have evaluated the relationship between different clinical expressions of classical ALS and measurements of brain cortical thickness. Cortical thickness analysis was conducted from 3D-MRI using FreeSurfer software in 29 ALS patients and 20 healthy controls. We explored three clinical traits of the disease, subdividing the patients into two groups for each of them: the bulbar or spinal onset, the higher or lower upper motor neuron burden, the faster or slower disease progression. We used both a whole brain vertex-wise analysis and a ROI analysis on primary motor areas. ALS patients showed cortical thinning in bilateral precentral gyrus, bilateral middle frontal gyrus, right superior temporal gyrus and right occipital cortex. ALS patients with higher upper motor neuron burden showed a significant cortical thinning in the right precentral gyrus and in other frontal extra-motor areas, compared to healthy controls. ALS patients with spinal onset showed a significant cortical thinning in the right precentral gyrus and paracentral lobule, compared to healthy controls. ALS patients with faster progressive disease showed a significant cortical thinning in widespread bilateral frontal and temporal areas, including the bilateral precentral gyrus, compared to healthy controls. Focusing on the primary motor areas, the ROI analysis revealed that the mean cortical thickness values were significantly reduced in ALS patients with higher upper motor neuron burden, spinal onset and faster disease progression related to healthy controls. In conclusion, the thickness of primary motor cortex could be a useful surrogate marker of upper motor neuron involvement in ALS; also our results suggest that cortical thinning in motor and non motor areas seem to reflect the clinical heterogeneity of the disease.

  13. Cortical thinning and clinical heterogeneity in amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Domenico Maria Mezzapesa

    Full Text Available Amyotrophic lateral sclerosis (ALS has heterogeneous clinical features that could be translated into specific patterns of brain atrophy. In the current study we have evaluated the relationship between different clinical expressions of classical ALS and measurements of brain cortical thickness. Cortical thickness analysis was conducted from 3D-MRI using FreeSurfer software in 29 ALS patients and 20 healthy controls. We explored three clinical traits of the disease, subdividing the patients into two groups for each of them: the bulbar or spinal onset, the higher or lower upper motor neuron burden, the faster or slower disease progression. We used both a whole brain vertex-wise analysis and a ROI analysis on primary motor areas. ALS patients showed cortical thinning in bilateral precentral gyrus, bilateral middle frontal gyrus, right superior temporal gyrus and right occipital cortex. ALS patients with higher upper motor neuron burden showed a significant cortical thinning in the right precentral gyrus and in other frontal extra-motor areas, compared to healthy controls. ALS patients with spinal onset showed a significant cortical thinning in the right precentral gyrus and paracentral lobule, compared to healthy controls. ALS patients with faster progressive disease showed a significant cortical thinning in widespread bilateral frontal and temporal areas, including the bilateral precentral gyrus, compared to healthy controls. Focusing on the primary motor areas, the ROI analysis revealed that the mean cortical thickness values were significantly reduced in ALS patients with higher upper motor neuron burden, spinal onset and faster disease progression related to healthy controls. In conclusion, the thickness of primary motor cortex could be a useful surrogate marker of upper motor neuron involvement in ALS; also our results suggest that cortical thinning in motor and non motor areas seem to reflect the clinical heterogeneity of the disease.

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

    International Nuclear Information System (INIS)

    Matias-Guiu, Jordi A.; Pytel, Vanesa; Galan, Lucia; Valles-Salgado, Maria; Guerrero, Antonio; Moreno-Ramos, Teresa; Matias-Guiu, Jorge; Cabrera-Martin, Maria Nieves; Carreras, Jose Luis

    2016-01-01

    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 18 F-fluorodeoxyglucose (FDG), and amyloid-PET with 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 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.)

  15. 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.)

  16. DREAM-Dependent Activation of Astrocytes in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Larrodé, Pilar; Calvo, Ana Cristina; Moreno-Martínez, Laura; de la Torre, Miriam; Moreno-García, Leticia; Molina, Nora; Castiella, Tomás; Iñiguez, Cristina; Pascual, Luis Fernando; Mena, Francisco Javier Miana; Zaragoza, Pilar; Y Cajal, Santiago Ramón; Osta, Rosario

    2018-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown origin and characterized by a relentless loss of motor neurons that causes a progressive muscle weakness until death. Among the several pathogenic mechanisms that have been related to ALS, a dysregulation of calcium-buffering proteins in motor neurons of the brain and spinal cord can make these neurons more vulnerable to disease progression. Downstream regulatory element antagonist modulator (DREAM) is a neuronal calcium-binding protein that plays multiple roles in the nucleus and cytosol. The main aim of this study was focused on the characterization of DREAM and glial fibrillary acid protein (GFAP) in the brain and spinal cord tissues from transgenic SOD1 G93A mice and ALS patients to unravel its potential role under neurodegenerative conditions. The DREAM and GFAP levels in the spinal cord and different brain areas from transgenic SOD1 G93A mice and ALS patients were analyzed by Western blot and immunohistochemistry. Our findings suggest that the calcium-dependent excitotoxicity progressively enhanced in the CNS in ALS could modulate the multifunctional nature of DREAM, strengthening its apoptotic way of action in both motor neurons and astrocytes, which could act as an additional factor to increase neuronal damage. The direct crosstalk between astrocytes and motor neurons can become vulnerable under neurodegenerative conditions, and DREAM could act as an additional switch to enhance motor neuron loss. Together, these findings could pave the way to further study the molecular targets of DREAM to find novel therapeutic strategies to fight ALS.

  17. Edaravone and its clinical development for amyotrophic lateral sclerosis.

    Science.gov (United States)

    Takei, Koji; Watanabe, Kazutoshi; Yuki, Satoshi; Akimoto, Makoto; Sakata, Takeshi; Palumbo, Joseph

    2017-10-01

    The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.

  18. Amyotrophic lateral sclerosis and assisted ventilation: how patients decide.

    Science.gov (United States)

    Lemoignan, Josée; Ells, Carolyn

    2010-06-01

    Throughout the course of their illness, people with amyotrophic lateral sclerosis (ALS) must make many treatment decisions; however, none has such a significant impact on quality of life and survival as decisions about assisted ventilation. The purpose of this study was to better understand the experience of decision-making about assisted ventilation for ALS patients. Using qualitative phenomenology methodology, 10 semi-structured interviews were conducted with persons with ALS and their caregivers to elicit factors that are pertinent to their decision-making process about assisted ventilation. Six main themes emerged from the interviews. (1) the meaning of the intervention - participants made a sharp distinction between non-invasive ventilation, which they viewed as a means to relieve symptoms of respiratory failure, and invasive ventilation, which they viewed as taking over their breathing and thereby saving their life when they otherwise would die, (2) the importance of context - including functional status, available supports, and financial implications, (3) the importance of values - with respect to communication, relationships, autonomy, life, and quality of life, (4) the effect of fears - particularly respiratory distress, chocking, running out of air, and the process of death itself, (5) the need for information - how use of assisted ventilation would impact daily life, how death from respiratory failure would occur, how caregivers and persons with ALS differ in their information needs and common misconceptions, and (6) adaptation to or acceptance of the intervention - a lengthy process that involved gradual familiarization with the equipment and its benefits. People with ALS and caregivers value autonomy in decision-making about assisted ventilation. Their decision-making process is neither wholly rational nor self-interested, and includes factors that health professionals should anticipate and address. Discussions about assisted ventilation and timing

  19. Longitudinal modeling to predict vital capacity in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Jahandideh, Samad; Taylor, Albert A; Beaulieu, Danielle; Keymer, Mike; Meng, Lisa; Bian, Amy; Atassi, Nazem; Andrews, Jinsy; Ennist, David L

    2018-05-01

    Death in amyotrophic lateral sclerosis (ALS) patients is related to respiratory failure, which is assessed in clinical settings by measuring vital capacity. We developed ALS-VC, a modeling tool for longitudinal prediction of vital capacity in ALS patients. A gradient boosting machine (GBM) model was trained using the PRO-ACT (Pooled Resource Open-access ALS Clinical Trials) database of over 10,000 ALS patient records. We hypothesized that a reliable vital capacity predictive model could be developed using PRO-ACT. The model was used to compare FVC predictions with a 30-day run-in period to predictions made from just baseline. The internal root mean square deviations (RMSD) of the run-in and baseline models were 0.534 and 0.539, respectively, across the 7L FVC range captured in PRO-ACT. The RMSDs of the run-in and baseline models using an unrelated, contemporary external validation dataset (0.553 and 0.538, respectively) were comparable to the internal validation. The model was shown to have similar accuracy for predicting SVC (RMSD = 0.562). The most important features for both run-in and baseline models were "Baseline forced vital capacity" and "Days since baseline." We developed ALS-VC, a GBM model trained with the PRO-ACT ALS dataset that provides vital capacity predictions generalizable to external datasets. The ALS-VC model could be helpful in advising and counseling patients, and, in clinical trials, it could be used to generate virtual control arms against which observed outcomes could be compared, or used to stratify patients into slowly, average, and rapidly progressing subgroups.

  20. Increased aluminum content in the spinal cord of amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam and in the Kii Peninsula of Japan

    Energy Technology Data Exchange (ETDEWEB)

    Wakayama, Ikuro; Yoshida, Sohei [Wakayama Medical Coll. (Japan); Sasajima, Kazuhisa; Takada, Jitsuya; Yoshida, Koichi

    1994-07-01

    Aluminum content in the lumbar spinal cord of patients with amyotrophic lateral sclerosis(ALS) and Parkinsonism-dementia(PD) in the Kii Peninsula of Japan and in the island of Guam was measured using a particle induced X-ray emission analysis. We demonstrated that aluminum content was increased in the spinal cord of patients with ALS in two foci of the western Pacific, indicating aluminum to be a important factor in the process of spinal motor neuron degeneration. (author).

  1. Increased aluminum content in the spinal cord of amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam and in the Kii Peninsula of Japan

    International Nuclear Information System (INIS)

    Wakayama, Ikuro; Yoshida, Sohei; Sasajima, Kazuhisa; Takada, Jitsuya; Yoshida, Koichi.

    1994-01-01

    Aluminum content in the lumbar spinal cord of patients with amyotrophic lateral sclerosis(ALS) and Parkinsonism-dementia(PD) in the Kii Peninsula of Japan and in the island of Guam was measured using a particle induced X-ray emission analysis. We demonstrated that aluminum content was increased in the spinal cord of patients with ALS in two foci of the western Pacific, indicating aluminum to be a important factor in the process of spinal motor neuron degeneration. (author)

  2. Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Alshikho, Mohamad J; Zürcher, Nicole R; Loggia, Marco L; Cernasov, Paul; Chonde, Daniel B; Izquierdo Garcia, David; Yasek, Julia E; Akeju, Oluwaseun; Catana, Ciprian; Rosen, Bruce R; Cudkowicz, Merit E; Hooker, Jacob M; Atassi, Nazem

    2016-12-13

    In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants. Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [ 11 C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [ 11 C]-PBR28 uptake. In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [ 11 C]-PBR28 binding in the left motor cortex was correlated with FA (r = -0.68, p < 0.05) and cortical thickness (r = -0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = -0.77, p < 0.05), and cortical thickness (r = -0.75, p < 0.05) in the motor cortex. Increased uptake of the glial marker [ 11 C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS. © 2016 American Academy of Neurology.

  3. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study.

    Science.gov (United States)

    Al-Chalabi, Ammar; Calvo, Andrea; Chio, Adriano; Colville, Shuna; Ellis, Cathy M; Hardiman, Orla; Heverin, Mark; Howard, Robin S; Huisman, Mark H B; Keren, Noa; Leigh, P Nigel; Mazzini, Letizia; Mora, Gabriele; Orrell, Richard W; Rooney, James; Scott, Kirsten M; Scotton, William J; Seelen, Meinie; Shaw, Christopher E; Sidle, Katie S; Swingler, Robert; Tsuda, Miho; Veldink, Jan H; Visser, Anne E; van den Berg, Leonard H; Pearce, Neil

    2014-11-01

    Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process. We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995-2012), the Netherlands (2006-12), Italy (1995-2004), Scotland (1989-98), and England (2002-09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register. We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r(2)=0·95, Ireland r(2)=0·99, Italy r(2)=0·95, the Netherlands r(2)=0·99, and Scotland r(2)=0·97; overall r(2)=0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5-5·0), with similar estimates for men (4·6, 4·3-4·9) and women (5·0, 4·5-5·5). A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues. UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the

  4. 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)

  5. 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

  6. Healthcare Professionals’ Views on the Provision of Gastrostomy and Noninvasive Ventilation to Amyotrophic Lateral Sclerosis Patients in England, Wales, and Northern Ireland

    OpenAIRE

    Ruffell, Tamatha; Martin, Naomi; Janssen, Anna; Wijesekera, Lokesh; Knights, Catherine; Burman, Rachel; Oliver, David J.; Al-Chalabi, Ammar; Goldstein, Laura

    2013-01-01

    Gastrostomy and noninvasive ventilation (NIV) are recommended interventions for the management of symptoms associated with amyotrophic lateral sclerosis (ALS). This study aimed to quantify the views of a range of healthcare professionals (HCPs) on the provision of these interventions in the United Kingdom. A total of 177 HCPs participated in an online survey. Significant differences were found between medical and allied HCPs’ views on: whether HCPs adhere to policy and accept legal constraint...

  7. 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.

  8. Decrease in N-acetylaspartate/creatine ratio in the motor area and the frontal lobe in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Abe, K.; Takanashi, M.; Yanagihara, T.; Watanabe, Y.; Tanaka, H.; Fujita, N.; Hirabuki, N.

    2001-01-01

    We studied whether N-acetylaspartate (NAA), a neuronal marker, is reduced in the brain of 14 patients with clinically definite amyotrophic lateral sclerosis (ALS) and whether NAA levels in the motor area and frontal lobe correlate with the clinical features, including frontal lobe function. We also studied 14 normal controls were evaluated. We obtained peak integrals in 1 H magnetic resonance spectroscopy (MRS) for NAA, creatine (Cr), and choline-containing compounds (Cho). Severity of the disease was determined using the manual muscle strength test, and the Norris limb and bulbar scales. In the patients, the NAA/Cr ratio was reduced in the motor area and frontal lobe, while the Cho/Cr ratio was normal throughout the brain. There were significant correlations between the NAA/Cr ratio in the motor area and the Norris limb scale (r = 0.50; P < 0.01) and between the NAA/Cr ratio in the frontal lobe and the number of categories achieved in the Wisconsin Card Sorting test (r = 0.71; P < 0.05), implying frontal lobe dysfunction. These correlations suggest that a reduced NAA/Cr ratio is a marker of cortical neuronal loss and dysfunction in ALS. (orig.)

  9. Decrease in N-acetylaspartate/creatine ratio in the motor area and the frontal lobe in amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Abe, K.; Takanashi, M.; Yanagihara, T. [Dept. of Neurology, Osaka University Graduate School of Medicine (Japan); Watanabe, Y.; Tanaka, H.; Fujita, N.; Hirabuki, N. [Dept. of Radiology, Osaka University Graduate School of Medicine (Japan)

    2001-07-01

    We studied whether N-acetylaspartate (NAA), a neuronal marker, is reduced in the brain of 14 patients with clinically definite amyotrophic lateral sclerosis (ALS) and whether NAA levels in the motor area and frontal lobe correlate with the clinical features, including frontal lobe function. We also studied 14 normal controls were evaluated. We obtained peak integrals in {sup 1}H magnetic resonance spectroscopy (MRS) for NAA, creatine (Cr), and choline-containing compounds (Cho). Severity of the disease was determined using the manual muscle strength test, and the Norris limb and bulbar scales. In the patients, the NAA/Cr ratio was reduced in the motor area and frontal lobe, while the Cho/Cr ratio was normal throughout the brain. There were significant correlations between the NAA/Cr ratio in the motor area and the Norris limb scale (r = 0.50; P < 0.01) and between the NAA/Cr ratio in the frontal lobe and the number of categories achieved in the Wisconsin Card Sorting test (r = 0.71; P < 0.05), implying frontal lobe dysfunction. These correlations suggest that a reduced NAA/Cr ratio is a marker of cortical neuronal loss and dysfunction in ALS. (orig.)

  10. Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)? A post-mortem study of 80 ALS patients

    OpenAIRE

    Burkhardt, Christian; Neuwirth, Christoph; Sommacal, Andreas; Andersen, Peter M.; Weber, Markus

    2017-01-01

    Background: Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown. Objective: To investigate the effect of NIV and PEG on survival and causes of death in ALS patients. Methods: Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015. Fort...

  11. Atypical Initial Presentation of Painful Muscle Cramps in a Patient with Amyotrophic Lateral Sclerosis: A Case Report and Brief Review of the Literature

    OpenAIRE

    Kuzel, Aaron R; Lodhi, Muhammad Uzair; Syed, Intekhab Askari; Rahim, Mustafa

    2017-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized clinically by progressive muscle weakness that can occur proximally or distally in either the upper or lower extremities. It includes both upper motor neuron signs (spasticity, hyperreflexia, clonus, and Babinski sign) and lower motor neuron signs (atrophy, weakness, and muscle fasciculation). Initial presentation of progressively painful muscle cramps should lead the physician to screen for other signs of amyot...

  12. Executive deficits, not processing speed relates to abnormalities in distinct prefrontal tracts in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Pettit, Lewis D; Bastin, Mark E; Smith, Colin; Bak, Thomas H; Gillingwater, Thomas H; Abrahams, Sharon

    2013-11-01

    Cognitive impairment in amyotrophic lateral sclerosis is characterized by deficits on tests of executive function; however, the contribution of abnormal processing speed is unknown. Methods are confounded by tasks that depend on motor speed in patients with physical disability. Structural and functional magnetic resonance imaging studies have revealed multi-system cerebral involvement, with evidence of reduced white matter volume and integrity in predominant frontotemporal regions. The current study has two aims. First, to investigate whether cognitive impairments in amyotrophic lateral sclerosis are due to executive dysfunction or slowed processing speed using methodology that accommodates motor disability. This is achieved using a dual-task paradigm and tasks that manipulate stimulus presentation times and do not rely on response motor speed. Second, to identify relationships between specific cognitive impairments and the integrity of distinct white matter tracts. Thirty patients with amyotrophic lateral sclerosis and 30 age- and education-matched control subjects were administered an experimental dual-task procedure that combined a visual inspection time task and digit recall. In addition, measures of executive function (including letter fluency) and processing speed (visual inspection time and rapid serial letter identification) were administered. Integrity of white matter tracts was determined using region of interest analyses of diffusion tensor magnetic resonance imaging data. Patients with amyotrophic lateral sclerosis did not show impairments on tests of processing speed, but executive deficits were revealed once visual inspection time was combined with digit recall (dual-task) and in letter fluency. In addition to the corticospinal tracts, significant differences in fractional anisotropy and mean diffusivity were found between groups in a number of prefrontal and temporal white matter tracts including the anterior cingulate, anterior thalamic radiation

  13. 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 Available FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS, Ewing's sarcoma (EWS, and TATA-binding protein-associated factor 15 (TAF15. Mutations in the copper/zinc superoxide dismutase (SOD1, TAR DNA-binding protein 43 (TDP-43, and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS, a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available. Epidemiological studies indicate that the consumption of tea is associated with a reduced risk of developing neurodegenerative diseases. The results of this study revealed that components of a pu-erh tea extract (PTE interacted with FET family proteins but not with TDP-43 or SOD1. PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1. The most frequently occurring ALS-linked FUS/TLS mutant protein, R521C FUS/TLS, was also degraded in the presence of PTE. Furthermore, ammonium chloride, a lysosome inhibitor, but not lactacystin, a proteasome inhibitor, reduced the degradation of FUS/TLS protein by PTE. PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions. These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins.

  14. MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis.

    Science.gov (United States)

    MacNair, Laura; Xiao, Shangxi; Miletic, Denise; Ghani, Mahdi; Julien, Jean-Pierre; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Robertson, Janice

    2016-01-01

    Tar DNA-binding protein 43 (TDP-43) is an RNA-binding protein normally localized to the nucleus of cells, where it elicits functions related to RNA metabolism such as transcriptional regulation and alternative splicing. In amyotrophic lateral sclerosis, TDP-43 is mislocalized from the nucleus to the cytoplasm of diseased motor neurons, forming ubiquitinated inclusions. Although mutations in the gene encoding TDP-43, TARDBP, are found in amyotrophic lateral sclerosis, these are rare. However, TDP-43 pathology is common to over 95% of amyotrophic lateral sclerosis cases, suggesting that abnormalities of TDP-43 play an active role in disease pathogenesis. It is our hypothesis that a loss of TDP-43 from the nucleus of affected motor neurons in amyotrophic lateral sclerosis will lead to changes in RNA processing and expression. Identifying these changes could uncover molecular pathways that underpin motor neuron degeneration. Here we have used translating ribosome affinity purification coupled with microarray analysis to identify the mRNAs being actively translated in motor neurons of mutant TDP-43(A315T) mice compared to age-matched non-transgenic littermates. No significant changes were found at 5 months (presymptomatic) of age, but at 10 months (symptomatic) the translational profile revealed significant changes in genes involved in RNA metabolic process, immune response and cell cycle regulation. Of 28 differentially expressed genes, seven had a ≥ 2-fold change; four were validated by immunofluorescence labelling of motor neurons in TDP-43(A315T) mice, and two of these were confirmed by immunohistochemistry in amyotrophic lateral sclerosis cases. Both of these identified genes, DDX58 and MTHFSD, are RNA-binding proteins, and we show that TDP-43 binds to their respective mRNAs and we identify MTHFSD as a novel component of stress granules. This discovery-based approach has for the first time revealed translational changes in motor neurons of a TDP-43 mouse model

  15. The Role of Metal Binding in the Amyotrophic Lateral Sclerosis-Related Aggregation of Copper-Zinc Superoxide Dismutase

    Directory of Open Access Journals (Sweden)

    Ivana Sirangelo

    2017-08-01

    Full Text Available Protein misfolding and conformational changes are common hallmarks in many neurodegenerative diseases involving formation and deposition of toxic protein aggregates. Although many players are involved in the in vivo protein aggregation, physiological factors such as labile metal ions within the cellular environment are likely to play a key role. In this review, we elucidate the role of metal binding in the aggregation process of copper-zinc superoxide dismutase (SOD1 associated to amyotrophic lateral sclerosis (ALS. SOD1 is an extremely stable Cu-Zn metalloprotein in which metal binding is crucial for folding, enzymatic activity and maintenance of the native conformation. Indeed, demetalation in SOD1 is known to induce misfolding and aggregation in physiological conditions in vitro suggesting that metal binding could play a key role in the pathological aggregation of SOD1. In addition, this study includes recent advances on the role of aberrant metal coordination in promoting SOD1 aggregation, highlighting the influence of metal ion homeostasis in pathologic aggregation processes.

  16. 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

  17. Association of the hOGG1 Ser326Cys polymorphism with sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Coppedè, Fabio; Mancuso, Michelangelo; Lo Gerfo, Annalisa; Carlesi, Cecilia; Piazza, Selina; Rocchi, Anna; Petrozzi, Lucia; Nesti, Claudia; Micheli, Dario; Bacci, Andrea; Migliore, Lucia; Murri, Luigi; Siciliano, Gabriele

    2007-06-13

    Amyotropic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease causing the loss of motoneurons of the brain and the spinal cord. The etiology of ALS is still uncertain, but males are at increased risk for the disease than females. Several studies have suggested that motoneurons in ALS might be subjected to the double insult of increased DNA oxidative damage and deficiencies in DNA repair systems. Particularly, increased levels of 8-oxoguanine and impairments of the DNA base excision repair system have been observed in neurons of ALS patients. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. To evaluate the role of the hOGG1 Ser326Cys polymorphism in sporadic ALS (sALS), we screened 136 patients and 129 matched controls. In the total population, we observed association between both the Cys326 allele (p=0.02) and the combined Ser326Cys+Cys326Cys genotype (OR=1.65, 95% CI=1.06-2.88) and increased risk of disease. After stratification by gender, the Cys326 allele (p=0.01), both the Ser326Cys genotype (OR=2.14, 95% CI=1.09-4.19) and the combined Ser326Cys+Cys326Cys genotype (OR=2.15, 95% CI=1.16-4.01) were associated with sALS risk only in males. No significant association between the Ser326Cys polymorphism and disease phenotype, including age and site of onset and disease progression, was observed. Present results suggest a possible involvement of the hOGG1 Ser326Cys polymorphism in sALS pathogenesis.

  18. Advance care planning for patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Levi, Benjamin H; Simmons, Zachary; Hanna, Courtney; Brothers, Allyson; Lehman, Erik; Farace, Elana; Bain, Megan; Stewart, Renee; Green, Michael J

    2017-08-01

    To determine whether an advance care planning (ACP) decision-aid could improve communication about end-of-life treatment wishes between patients with amyotrophic lateral sclerosis (ALS) and their clinicians. Forty-four patients with ALS (>21, English-speaking, without dementia) engaged in ACP using an interactive computer based decision-aid. Before participants completed the intervention, and again three months later, their clinicians reviewed three clinical vignettes, and made treatment decisions (n = 18) for patients. After patients indicated their agreement with the team's decisions, concordance was calculated. The mean concordance between patient wishes and the clinical team decisions was significantly higher post-intervention (post = 91.9%, 95% CI = 87.8, 96.1, vs. pre = 52.4%, 95% CI = 41.9, 62.9; p <0.001). Clinical team members reported greater confidence that their decisions accurately represented each patient's wishes post-intervention (mean = 6.5) compared to pre-intervention (mean = 3.3, 1 = low, 10 = high, p <0.001). Patients reported high satisfaction (mean = 26.4, SD = 3.2; 6 = low, 30 = high) and low decisional conflict (mean = 28.8, SD = 8.2; 20 = low, 80 = high) with decisions about end-of-life care, and high satisfaction with the decision-aid (mean = 52.7, SD = 5.7, 20 = low, 60 = high). Patient knowledge regarding ACP increased post-intervention (pre = 47.8% correct responses vs. post = 66.3%; p <0.001) without adversely affecting patient anxiety or self-determination. A computer based ACP decision-aid can significantly improve clinicians' understanding of ALS patients' wishes with regard to end-of-life medical care.

  19. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia.

    Science.gov (United States)

    Dols-Icardo, Oriol; García-Redondo, Alberto; Rojas-García, Ricard; Sánchez-Valle, Raquel; Noguera, Aina; Gómez-Tortosa, Estrella; Pastor, Pau; Hernández, Isabel; Esteban-Pérez, Jesús; Suárez-Calvet, Marc; Antón-Aguirre, Sofía; Amer, Guillermo; Ortega-Cubero, Sara; Blesa, Rafael; Fortea, Juan; Alcolea, Daniel; Capdevila, Aura; Antonell, Anna; Lladó, Albert; Muñoz-Blanco, José Luís; Mora, Jesús S; Galán-Dávila, Lucía; Rodríguez De Rivera, Francisco Javier; Lleó, Alberto; Clarimón, Jordi

    2014-02-01

    Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.

  20. [Amyotrophic lateral sclerosis and exposure to metals and other occupational/environmental hazardous materials: state of the art].

    Science.gov (United States)

    Garzillo, Elpidio Maria; Miraglia, Nadia; Pedata, Paola; Feola, Daniela; Sannolo, Nicola; Lamberti, Monica

    2015-01-01

    In recent years, scientific literature has been giving more and more importance to the study of the occupational/environmental exposure to risk agents related to the onset of Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex. Aim of this work is to verify the state of art about the eventual role of occupational/environmental exposure to risk agents. Selected articles, on the basis of keywords, year of publication and topics, are related to occupational and environmental exposure to xenobiotics, and, in particular, to the exposure to heavy metals that could lead to neuronal damage mechanisms involved in ALS onset. The review shows that although the scientific production has increased the interest in the evaluation of extra-genetic causes of ALS onset, there are still few studies concerning the careful study of the work activities of the individual patient, and the inferences that can be drawn to date about the possible connection between occupational exposure to risk factors and the onset of ALS are still lacking.

  1. Measuring Neuromuscular Junction Functionality in the SOD1(G93A) Animal Model of Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Rizzuto, Emanuele; Pisu, Simona; Musarò, Antonio; Del Prete, Zaccaria

    2015-09-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to motor neuron degeneration, alteration in neuromuscular junctions (NMJs), muscle atrophy, and paralysis. To investigate the NMJ functionality in ALS we tested, in vitro, two innervated muscle types excised from SOD1(G93A) transgenic mice at the end-stage of the disease: the Soleus, a postural muscle almost completely paralyzed at that stage, and the diaphragm, which, on the contrary, is functional until death. To this aim we employed an experimental protocol that combined two types of electrical stimulation: the direct stimulation and the stimulation through the nerve. The technique we applied allowed us to determine the relevance of NMJ functionality separately from muscle contractile properties in SOD1(G93A) animal model. Functional measurements revealed that the muscle contractility of transgenic diaphragms is almost unaltered in comparison to control muscles, while transgenic Soleus muscles were severely compromised. In contrast, when stimulated via the nerve, both transgenic muscle types showed a strong decrease of the contraction force, a slowing down of the kinetic parameters, as well as alterations in the neurotransmission failure parameter. All together, these results confirm a severely impaired functionality in the SOD1(G93A) neuromuscular junctions.

  2. 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.

  3. Radio-sensitivity of the cells from amyotrophic lateral sclerosis model mice transfected with human mutant SOD1

    International Nuclear Information System (INIS)

    Wate, Reika; Ito, Hidefumi; Kusaka, Hirofumi; Takahashi, Sentaro; Kubota, Yoshihisa; Suetomi, Katsutoshi; Sato, Hiroshi; Okayasu, Ryuichi

    2005-01-01

    In order to clarify the possible involvement of oxidative damage induced by ionizing radiation in the onset and/or progression of familial amyotrophic lateral sclerosis (ALS), we studied radio-sensitivity in primary cells derived from ALS model mice expressing human mutant Cu/Zn superoxide dismutase (SOD1). The primary mouse cells expressed both mouse and the mutant human SOD1. The cell survival of the transgenic mice (with mutant SOD1), determined by counting cell numbers at a scheduled time after X-irradiation, is very similar to that of cells from wild type animals. The induction and repair of DNA damage in the transgenic cells, measured by single cell gel electrophoresis and pulsed field gel electrophoresis, are also similar to those of wild type cells. These results indicate that the human mutant SOD1 gene does not seem to contribute to the alteration of radio-sensitivity, at least in the fibroblastic cells used here. Although it is necessary to consider the difference in cell types between fibroblastic and neuronal cells, the present results may suggest that ionizing radiation is not primarily responsible for the onset of familial ALS with the SOD1 mutation, and that the excess risks are probably not a concern for radiation diagnosis and therapy in familial ALS patients. (author)

  4. Spontaneous brain activity in the sensorimotor cortex in amyotrophic lateral sclerosis can be negatively regulated by corticospinal fiber integrity.

    Science.gov (United States)

    Sako, Wataru; Abe, Takashi; Izumi, Yuishin; Yamazaki, Hiroki; Matsui, Naoko; Harada, Masafumi; Kaji, Ryuji

    2017-05-01

    Previous studies failed to detect reduced value of the amplitude of low frequency fluctuation (ALFF) derived from resting state functional magnetic resonance imaging in the primary motor cortex in amyotrophic lateral sclerosis (ALS) though primary motor cortex was mainly affected with ALS. We aimed to investigate the cause of masking the abnormality in the primary motor cortex in ALS and usefulness of ALFF for differential diagnosis among diseases showing muscle weakness. We enrolled ten patients with ALS and eleven disease controls showing muscle weakness. Voxel-wise analysis revealed that significant reduction of ALFF value was present in the right sensorimotor cortex in ALS. There was a significant negative correlation between ALFF value in the right sensorimotor cortex and fractional anisotropy (FA) value in the posterior limbs of the internal capsule (PLIC). For a diagnostic tool, the area under receiver operating characteristic curve improved if the ALS patients with disease duration >1 year were excluded. The present findings raised the possibility of usefulness of ALFF value in the sensorimotor cortex for differential diagnosis of ALS, and supported the notion that adjustment for FA value in the PLIC could improve accuracy.

  5. Incidence of amyotrophic lateral sclerosis in the province of Novara, Italy, and possible role of environmental pollution.

    Science.gov (United States)

    Tesauro, Marina; Consonni, Michela; Filippini, Tommaso; Mazzini, Letizia; Pisano, Fabrizio; Chiò, Adriano; Esposito, Aniello; Vinceti, Marco

    2017-05-01

    Based on nationwide death certificates, a cluster of amyotrophic lateral sclerosis (ALS) has been reported in the area of Briga (Novara province, northern Italy), known for its severe environmental contamination. We further investigated this finding, by following up with the collection of recent incidence ALS data in 2002-2012 of Novara province, also to assess the possible long-term effects of environmental pollution in that area. In the whole Novara province we identified 106 ALS cases, of which 35 were from the Briga area. Incidence rates of Novara province were 3.98, 5.14 and 2.97 for the total population, males and females, respectively, compared with the Briga area where they were 4.65, 4.27 and 4.98, respectively. The ratio of observed-to-expected ALS cases in the Briga area, using incidence of the rest of Novara province as a reference, was 1.17 (95% CI 0.81-1.62), with a value of 0.83 (95% CI 0.47-1.37) in males and 1.68 (95% CI 1.03-2.60) in females. Overall, our study did not confirm previous findings of an excess ALS incidence in an area characterised by severe environmental heavy metal pollution, and it suggests the need to interpret with caution clusters identified through mortality data.

  6. Botulinum toxin type A for the treatment of sialorrhoea in amyotrophic lateral sclerosis: a clinical and neurophysiological study.

    Science.gov (United States)

    Gilio, Francesca; Iacovelli, Elisa; Frasca, Vittorio; Gabriele, Maria; Giacomelli, Elena; Picchiori, Floriana; Soldo, Pietro; Cipriani, Anna Maria; Ruoppolo, Giovanni; Inghilleri, Maurizio

    2010-08-01

    Botulinum toxin type A (BoNT/A) has been proposed as an alternative treatment for sialorrhoea in patients with amyotrophic lateral sclerosis (ALS). In an open-label prospective study, BoNT/A was injected into the parotid glands bilaterally using anatomic landmarks in 26 ALS patients with bulbar symptoms. Two weeks after injection the severity of sialorrhoea and the related disability were evaluated subjectively and objectively. A group of healthy subjects acted as controls for saliva production. Patients also underwent electrophysiological tests to evaluate possible toxin effects in the nearby non-injected muscles by comparing the amplitude of compound motor action potentials (cMAPs) elicited by electrical stimulation and recorded from the orbicularis oculi and masseter muscles. After BoNT/A injections, of the 26 patients treated, 23 reported that the severity of sialorrhoea improved and the disabling symptoms diminished. Cotton roll weight also decreased after BoNT/A injection, suggesting a reduction in saliva production. Two patients complained of dry mouth. BoNT/A injection left the cMAP amplitude unchanged, suggesting that botulinum toxin does not significantly affect the non-injected facial and masticatory muscles. In conclusion, intraparotid anatomically-guided BoNT/A injection is an effective, easy, and safe treatment for sialorrhoea in patients with bulbar symptoms related to ALS.

  7. Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Review of Two Cases and the Associated Literature

    Directory of Open Access Journals (Sweden)

    Hongfei Tai

    2017-05-01

    Full Text Available ObjectiveTo describe the characteristics of patients with amyotrophic lateral sclerosis (ALS and myasthenia gravis (MG overlap syndrome and explore the relationship between the two diseases.MethodsWe conducted a search of medical records at Peking Union Medical University Hospital from 1983 to 2015 for coexistence of ALS and MG and searched the PubMed database for all literature describing ALS and MG overlap syndrome published through December 2016. We analyzed the clinical and neurophysiological characteristics of patients by groups according to strict diagnostic criteria.ResultsWe presented 2 patients in our database with combined ALS and MG, and together with 25 cases reported in the literature, the patients were divided into 4 groups: 12 patients with MG followed by ALS, 8 patients with ALS followed by MG, 5 ALS patients with false-positive anti-acetylcholine receptor, and the other 2 ALS patients with only myasthenia symptoms. Most patients had limb onset ALS, and myasthenia symptoms mainly affected ocular and bulbar muscles. Clinical and neurophysiological characteristics were summarized.ConclusionThese findings support the conclusion that immunological mechanisms and alterations in the neuromuscular junction are related to ALS pathogenesis.

  8. 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.

  9. Possible involvement of overexposure to environmental selenium in the etiology of amyotrophic lateral sclerosis: a short review

    Directory of Open Access Journals (Sweden)

    Marco Vinceti

    2010-01-01

    Full Text Available Excess exposure to the metalloid selenium (Se, a trace element with both toxicological and nutritional properties, has been implicated in the etiology of a human motor neuron disease of unknown origin and extremely severe prognosis, sporadic amyotrophic lateral sclerosis (ALS. This relation has been suggested on the basis of two epidemiologic investigations which found an increased risk of ALS associated with residence in a seleniferous area or with consumption of drinking water with unusually high levels of inorganic hexavalent Se, in South Dakota and in northern Italy respectively. Biological plausibility to a Se-ALS relation is provided by veterinary medicine observations and toxicological studies, showing that Se, particularly the inorganic forms, has a selective toxicity to motor neurons in swine and in cattle. Neurotoxic effects of Se species have also been demonstrated in laboratory studies and, for the inorganic forms, even at very low concentrations. Selenium has also been shown to affect muscle function in experimental animal models. Overall, these findings from the epidemiologic and the toxicological literature indicate that environmental Se, particularly in its inorganic forms and at unexpectedly low levels of exposure, might be a risk factor for ALS, suggesting the opportunity to further investigate this issue.

  10. Exploring the Use of Educational Material About Shoulder Dysfunction: A Quality Improvement Project in People With Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Burke, Katherine; Ellrodt, Amy Swartz; Levine, Jason; Adams, Taylor; Allis, Rebecca; Macmurdie, Ian; Paganoni, Sabrina

    2018-05-01

    Shoulder pain is a common secondary complication of amyotrophic lateral sclerosis (ALS) that can contribute to functional decline and decreased participation in daily activities. The purpose of this study was to assess the effectiveness of an educational brochure aimed at improving knowledge regarding shoulder pain and dysfunction in people with ALS. Participants completed a preintervention survey with questions regarding their knowledge of how ALS may affect their shoulders. After completing the presurvey, they were mailed a brochure that described shoulder health and range of motion and stretching exercises. Four weeks after receiving the brochure, participants were then asked to determine the effectiveness of the educational materials in terms of impact on shoulder-related knowledge and self-efficacy with regard to prevention of shoulder pain and dysfunction. More than 50% of participants reported pain, decreased range of motion, or weakness in at least one shoulder since being diagnosed with ALS. All participants were interested in receiving educational materials, and all agreed that the brochure was easy to interpret and understand, with most (87%) reporting that it was helpful. Educational brochures are one strategy to improve awareness about shoulder health and to educate patients with ALS about exercises that may help reduce shoulder pain and dysfunction.

  11. Amyotrophic lateral sclerosis in Slovenia – analysis of patient population at the Ljubljana Institute of Clinical Neurophysiology

    Directory of Open Access Journals (Sweden)

    Mojca Kirbiš

    2015-09-01

    Full Text Available Backgorund: Data on epidemiology and disease characteristics of amyotrophic lateral sclerosis (ALS are geographically limited and no systematically collected data exist for slovenian patients. We performed a retrospective descriptive study on clinical attributes and disease course of patients with ALS treated at the Institute of clinical neurophysiology (ICN, University Medical Centre Ljubljana since the foundation of a specialised ALS group.Methods:  All 271 patients treated at ICN in the 10-year period between 2003 and 2012 were analysed. Data on basic demographic characteristics, phenotype of disease onset, diagnostic delay, survival, family history, use of percutaneous gastrostomy (PEG, of non-invasive ventilation and of riluzole were obtained.Results:  Mean age at symptoms onset was 62.7 ± 11.4 years, median diagnostic delay 11 (IQ range  7–19 months and mean survival from time of enrolment 16.4 ± 15.1 months.  179 (66.1%patients had spinal onset disease and 71 (26.2% bulbar onset disease. Factors associated with longer survival were lower age at enrolment, longer diagnostic delay and use of PEG. The proportion of patients using non-invasive ventilatory support was rising through the analysed years.Conclusions: Disease characteristics and survival in our series are similar to data from other tertiary care centres. The need for non-invasive ventilatory support in ALS patients is increasing.

  12. 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.

  13. 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.

  14. [Our first experiences with intermittent assisted ventilation in patients with amyotrophic lateral sclerosis].

    Science.gov (United States)

    Treuheit, T; Bartels, C; Hoffmann, B; Welte, T

    1999-10-01

    Amyotrophic lateral sclerosis is one of the most frequent neuromuscular diseases in adults. Chronic respiratory failures is an almost compulsory symptom in the progression of this disease, and in association with pulmonary infections, responsible for the majority of deaths. We report on a series of 43 patients. An advanced stage of clinical disease was seen in half of them. After detection of respiratory failure corresponding to the guidelines of muscle centres of the DGM (Deutsche Gesellschaft für Muskelerkrankungen), seven patients (16.3%) were willing to be provided with a system for intermittent non-invasive ventilation. All patients achieved stabilisation of respiratory function, both with respect to the normalisation of arterial gases and subjective improvement of well-being. During the course of treatment four patients deliberately underwent permanent invasive ventilation. In our opinion home ventilation is a valid additional tool in the palliative treatment of amyotrophic lateral sclerosis. The treatment, however, must be supported by an interdisciplinary team.

  15. Place of death in patients with amyotrophic lateral sclerosis

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    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

  16. TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Williams, Stephanie M; Khan, Galam; Harris, Brent T; Ravits, John; Sierks, Michael R

    2017-01-25

    TDP-43 aggregates accumulate in individuals affected by amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, representing potential diagnostic and therapeutic targets. Using an atomic force microscopy based biopanning protocol developed in our lab, we previously isolated 23 TDP-43 reactive antibody fragments with preference for human ALS brain tissue relative to frontotemporal dementia, a related neurodegeneration, and healthy samples from phage-displayed single chain antibody fragment (scFv) libraries. Here we further characterize the binding specificity of these different scFvs and identify which ones have promise for detecting ALS biomarkers in human brain tissue and plasma samples. We developed a sensitive capture ELISA for detection of different disease related TDP-43 variants using the scFvs identified from the ALS biopanning. We show that a wide variety of disease selective TDP-43 variants are present in ALS as the scFvs show different reactivity profiles amongst the ALS cases. When assaying individual human brain tissue cases, three scFvs (ALS-TDP6, ALS-TDP10 and ALS-TDP14) reacted with all the ALS cases and 12 others reacted with the majority of the ALS cases, and none of the scFvs reacted with any control samples. When assaying individual human plasma samples, 9 different scFvs reacted with all the sporadic ALS samples and again none of them reacted with any control samples. These 9 different scFvs had different patterns of reactivity with plasma samples obtained from chromosome 9 open reading frame 72 (c9orf72) cases indicating that these familial ALS genetic variants may display different TDP-43 pathology than sporadic ALS cases. These results indicated that a range of disease specific TDP-43 variants are generated in ALS patients with different variants being generated in sporadic and familial cases. We show that a small panel of scFvs recognizing different TDP-43 variants can generate a neuropathological and plasma biomarker

  17. 1H-MR spectroscopy study in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Han Jing; Ma Lin; Yu Shengyuan

    2009-01-01

    Objective: To characterize the features of proton magnetic resonance spectroscopy ( 1 H-MRS) on amyotrophic lateral sclerosis (ALS) and its correlations with clinical scale. Methods: Fifteen patients with definite or probable ALS and 15 age and gender matched normal controls were enrolled. 1 H-MRS was performed on a 3.0 T GE imaging system (GE Medical System, Milwaukee, Wisconsin, USA). TE-averaged point resolved selective spectroscopy was used. N-acetylaspartate (NAA), creatine (Cr), Glu and Glx (glutamate + glutamine) values of subcortical motor area and posterior limb of the internal capsule were acquired, t test was used to compare differences between groups, the correlations between the above values and clinical scale were analyzed. Results: The motor area and posterior limb of the internal capsule in ALS patients had significantly lower NAA/Cr (1.91±0.34, 1.53±0.17) compared with normal subjects (2.23±0.33, 1.66±0.07) (t=4.25,2.90,P=0.00,0.01). ALS patients had significantly higher Glu/Cr (0.34±0.05, 0.29±0.06) and Glx/Cr (0.40±0.04, 0.33±0.06), compared with normal subjects (0.30±0.03,0.25±0.04) and (0.32±0.05,0.26±0.03) (t=2.56, 2.40,7.34,5.30, P=0.02,0.03,0.00,0.00). The Norris scale of ALS patients were 57±8, ALSFRS were 29±4. The Norris scale was negatively correlated with Glx/Cr of primary motor cortex by lineal correlation analysis (r=-0.75, P=0.00), while ALSFRS had no correlation with Glx/Cr. Conclusions: Neuronal loss and Glu + Gln increase can be detected by using proton MRS in ALS patients. 1 H-MRS is an useful tool in reflecting the characteristic changes of metabolite in ALS. (authors)

  18. 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

  19. Analysis of the diagnostic pathway and delay in patients with amyotrophic lateral sclerosis in the Valencian Community.

    Science.gov (United States)

    Vázquez-Costa, J F; Martínez-Molina, M; Fernández-Polo, M; Fornés-Ferrer, V; Frasquet-Carrera, M; Sevilla-Mantecón, T

    2018-06-11

    Amyotrophic lateral sclerosis (ALS) is an insidious, clinically heterogeneous neurodegenerative disease associated with a diagnostic delay of approximately 12 months. No study conducted to date has analysed the diagnostic pathway in Spain. We gathered data on variables related to the diagnostic pathway and delay for patients diagnosed with ALS between October 2013 and July 2017. The study included 143 patients with ALS (57% men; 68% spinal onset). Patients were diagnosed in public centres in 86% of cases and in private centres in 14%.The mean diagnostic delay was 13.1 months (median 11.7). Patients were examined by neurologists a mean time of 7.9 months after symptom onset, with diagnosis being made 5.2 months later. Half of all patients underwent unnecessary diagnostic tests and multiple electrophysiological studies before diagnosis was established. Diagnostic delay was longer in cases of spinal onset (P = .008) due to onset of the disease in the lower limbs. No differences were found between the public and private healthcare systems (P = .897). The diagnostic delay in ALS in Spain is similar to that of neighboring countries and seems to depend on disease-related factors, not on the healthcare system. Patients with lower-limb onset ALS constitute the greatest diagnostic challenge. Misdiagnosis is frequent, and partly attributable to an incorrect approach or erroneous interpretation of electrophysiological studies. Specific training programmes for neurologists and general neurophysiologists and early referral to reference centers may help to reduce diagnostic delay. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  20. Aberration of miRNAs Expression in Leukocytes from Sporadic Amyotrophic Lateral Sclerosis

    OpenAIRE

    Chen, YongPing; Wei, QianQian; Chen, XuePing; Li, ChunYu; Cao, Bei; Ou, RuWei; Hadano, Shinji; Shang, Hui-Fang

    2016-01-01

    Background: Accumulating evidence indicates that miRNAs play an important role in the development of amyotrophic lateral sclerosis (ALS). Most of previous studies on miRNA dysregulation in ALS focused on the alterative expression in ALS animal model or in limited samples from European patients with ALS. In the present study, the miRNA expression profiles were investigated in Chinese ALS patients to explore leukocytes miRNAs as a potential biomarker for the diagnosis of ALS. Methods: We ana...

  1. Masticatory muscle pain and progressive mouth opening limitation caused by amyotrophic lateral sclerosis: a case report.

    Science.gov (United States)

    Pang, Kang Mi; Park, Ji Woon

    2015-01-01

    This article reports a case of masticatory muscle pain and progressive limited mouth opening secondary to amyotrophic lateral sclerosis (ALS), popularly known as Lou Gehrig's disease. The symptoms were first mistaken as those of temporomandibular disorders, before fatty degeneration of all masticatory muscles were discovered on magnetic resonance imaging (MRI). ALS should be considered in the differential diagnosis process when the patient presents with longstanding progressive mouth opening limitation associated with pain. MRI could facilitate the diagnostic process.

  2. 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...

  3. Is chronic ventilatory support really effective in patients with amyotrophic lateral sclerosis?

    OpenAIRE

    Hazenberg, A.; Kerstjens, H. A. M.; Prins, S. C. L.; Vermeulen, K. M.; Wijkstra, P. J.

    2016-01-01

    Most patients with amyotrophic lateral sclerosis (ALS) develop respiratory insufficiency in the advanced stage of their disease. Non-invasive ventilation (NIV) is commonly regarded to be a treatment that is effective in reducing these complaints. To assess whether the effect of NIV on gas exchange and quality of life (QOL) is different in patients with ALS versus without ALS. A post hoc analysis was done with data from a previously published trial, in which all patients were instituted on NIV...

  4. Amyotrophic Lateral Sclerosis and Organ Donation: Is There Risk of Disease Transmission?

    OpenAIRE

    Holmes, Brandon B.; Diamond, Marc I.

    2012-01-01

    A new protocol suggests that patients with amyotrophic lateral sclerosis (ALS) are a viable source of tissue for organ transplantation. However, multiple lines of evidence suggest that many neurodegenerative diseases, including ALS, might progress due to transcellular propagation of protein aggregation among neurons. Transmission of the disease state from donor to host thus may be possible under the permissive circumstances of graft transplantation. We argue for careful patient selection and ...

  5. Hypermetabolism is a deleterious prognostic factor in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Jésus, P; Fayemendy, P; Nicol, M; Lautrette, G; Sourisseau, H; Preux, P-M; Desport, J-C; Marin, B; Couratier, P

    2018-01-01

    The aim of this study was to investigate patients with amyotrophic lateral sclerosis in order to determine their nutritional, neurological and respiratory parameters, and survival according to metabolic level. Nutritional assessment included resting energy expenditure (REE) measured by indirect calorimetry [hypermetabolism if REE variation (ΔREE) > 10%] and fat mass (FM) using impedancemetry. Neurological assessment included the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score. Survival analysis used the Kaplan-Meier method and multivariate Cox model. A total of 315 patients were analysed. Median age at diagnosis was 65.9 years and 55.2% of patients were hypermetabolic. With regard to the metabolic level (ΔREE: 20%), patients with ΔREE > 20% initially had a lower FM(29.7% vs. 32.1% in those with ΔREE ≤10%; P = 0.0054). During follow-up, the median slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised tended to worsen more in patients with ΔREE > 20% (-1.4 vs. -1.0 points/month in those with ΔREE ≤10%; P = 0.07). Overall median survival since diagnosis was 18.4 months. ΔREE > 20% tended to increase the risk of dying compared with ΔREE ≤10% (hazard ratio, 1.33; P = 0.055). In multivariate analysis, an increased REE:FM ratio was independently associated with death (hazard ratio, 1.005; P = 0.001). Hypermetabolism is present in more than half of patients with amyotrophic lateral sclerosis. It modifies the body composition at diagnosis, and patients with hypermetabolism >20% have a worse prognosis than those without hypermetabolism. © 2017 EAN.

  6. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.

    Science.gov (United States)

    Kabashi, Edor; Valdmanis, Paul N; Dion, Patrick; Spiegelman, Dan; McConkey, Brendan J; Vande Velde, Christine; Bouchard, Jean-Pierre; Lacomblez, Lucette; Pochigaeva, Ksenia; Salachas, Francois; Pradat, Pierre-Francois; Camu, William; Meininger, Vincent; Dupre, Nicolas; Rouleau, Guy A

    2008-05-01

    Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.

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

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    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.

  8. Illness trajectories in patients with amyotrophic lateral sclerosis: How illness progression is related to life narratives and interpersonal relationships.

    Science.gov (United States)

    Cipolletta, Sabrina; Gammino, Giorgia Rosamaria; Palmieri, Arianna

    2017-12-01

    To identify illness trajectories in amyotrophic lateral sclerosis by analysing personal, social and functional dimensions related to amyotrophic lateral sclerosis progression. Previous studies have considered some psychological distinct variables that may moderate illness progression, but no research has combined an extensive qualitative understanding of amyotrophic lateral sclerosis patients' psychological characteristics and illness progression. A mixed-methods approach was used to combine quantitative and qualitative measures. Illness progression was assessed through a longitudinal design. Eighteen patients with amyotrophic lateral sclerosis attending a Neurology Department in northern Italy participated in the study. Semi-structured interviews to explore personal experience, and dependency grids to assess the distribution of dependency; ALSFRS-R and neuropsychological screening were, respectively, used to measure physical and cognitive impairment. To assess the progression of the disease, ALSFRS-R was re-administered after 8 months and mortality rate was considered. Data were analysed using the grounded theory approach. Illness progression changed according to the perception of the disease, the trust placed in medical care, self-construction and the distribution of dependency. Based on these categories, cases that had similar experiences were grouped, and four illness trajectories were identified: aggressiveness, threat, constriction and guilt. The findings suggest that it is possible to identify different illness trajectories in amyotrophic lateral sclerosis. Personalised intervention strategies may be construed based on the different trajectories identified. © 2017 John Wiley & Sons Ltd.

  9. Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Parry, Gareth J; Rodrigues, Cecilia M P; Aranha, Marcia M; Hilbert, Sarah J; Davey, Cynthia; Kelkar, Praful; Low, Walter C; Steer, Clifford J

    2010-01-01

    Amyotrophic lateral sclerosis is a progressive degenerative disease, which typically leads to death in 3 to 5 years. Neuronal cell death offers a potential target for therapeutic intervention. Ursodeoxycholic acid is a cytoprotective, endogenous bile acid that has been shown to be neuroprotective in experimental Huntington and Alzheimer diseases, retinal degeneration, and ischemic and hemorrhagic stroke. The objective of this research was to study the safety and the tolerability of ursodeoxycholic acid in amyotrophic lateral sclerosis and document effective and dose-dependent cerebrospinal fluid penetration. Eighteen patients were randomly assigned to receive ursodeoxycholic acid at doses of 15, 30, and 50 mg/kg of body weight per day. Serum and cerebrospinal fluid were obtained for analysis after 4 weeks of treatment. Treatment-emergent clinical and laboratory events were monitored weekly. Our data indicated that ursodeoxycholic acid is well tolerated by all subjects at all doses. We also showed that ursodeoxycholic acid is well absorbed after oral administration and crosses the blood-brain barrier in a dose-dependent manner. These results show excellent safety and tolerability of ursodeoxycholic acid. The drug penetrates the cerebrospinal fluid in a dose-dependent manner. A large, placebo-controlled clinical trial is needed to assess the efficacy of ursodeoxycholic acid in treating amyotrophic lateral sclerosis.

  10. System xC- is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice.

    Science.gov (United States)

    Mesci, Pinar; Zaïdi, Sakina; Lobsiger, Christian S; Millecamps, Stéphanie; Escartin, Carole; Seilhean, Danielle; Sato, Hideyo; Mallat, Michel; Boillée, Séverine

    2015-01-01

    Amyotrophic lateral sclerosis is the most common adult-onset motor neuron disease and evidence from mice expressing amyotrophic lateral sclerosis-causing SOD1 mutations suggest that neurodegeneration is a non-cell autonomous process where microglial cells influence disease progression. However, microglial-derived neurotoxic factors still remain largely unidentified in amyotrophic lateral sclerosis. With excitotoxicity being a major mechanism proposed to cause motor neuron death in amyotrophic lateral sclerosis, our hypothesis was that excessive glutamate release by activated microglia through their system [Formula: see text] (a cystine/glutamate antiporter with the specific subunit xCT/Slc7a11) could contribute to neurodegeneration. Here we show that xCT expression is enriched in microglia compared to total mouse spinal cord and absent from motor neurons. Activated microglia induced xCT expression and during disease, xCT levels were increased in both spinal cord and isolated microglia from mutant SOD1 amyotrophic lateral sclerosis mice. Expression of xCT was also detectable in spinal cord post-mortem tissues of patients with amyotrophic lateral sclerosis and correlated with increased inflammation. Genetic deletion of xCT in mice demonstrated that activated microglia released glutamate mainly through system [Formula: see text]. Interestingly, xCT deletion also led to decreased production of specific microglial pro-inflammatory/neurotoxic factors including nitric oxide, TNFa and IL6, whereas expression of anti-inflammatory/neuroprotective markers such as Ym1/Chil3 were increased, indicating that xCT regulates microglial functions. In amyotrophic lateral sclerosis mice, xCT deletion surprisingly led to earlier symptom onset but, importantly, this was followed by a significantly slowed progressive disease phase, which resulted in more surviving motor neurons. These results are consistent with a deleterious contribution of microglial-derived glutamate during symptomatic

  11. 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.

  12. 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

  13. Temporal trend of amyotrophic lateral sclerosis incidence in southern Europe: a population study in the health district of Ferrara, Italy.

    Science.gov (United States)

    Govoni, Vittorio; Cesnik, Edward; Casetta, Ilaria; Tugnoli, Valeria; Tola, Maria Rosaria; Granieri, Enrico

    2012-08-01

    Data about the temporal trend of amyotrophic lateral sclerosis (ALS) incidence in southern Europe are scarce. Incidence studies on ALS have been carried out in the health district of Ferrara, Italy, since 1960s. We expanded the previous studies from 1964 to 2009. The study was prospective with a subsequent retrospective intensive survey of multiple sources of case ascertainment. All patients with a definite and probable ALS according to the original El Escorial criteria were selected. There were 130 incident cases in the years 1964-2009 giving an average annual crude incidence of 1.82 per 100,000 population (95% CI 1.53-2.17). An incidence increase during the study period was estimated in women (χ(2) test for trend = 7.19, p < 0.01) and in the elderly (χ(2) test for trend = 7.803, p < 0.01). The age-adjusted incidence was stable over time in both women (1.19 per 100,000, 95% CI 0.90-1.52) and men (1.45 per 100,000, 95% CI 0.12-1.84). The annual number of new ALS cases in the study population followed the Poisson distribution in both sexes as well as in the elderly group of the population. The present findings suggest that ALS incidence is nearly stable over time. The crude incidence increase we estimated over time among women is mainly explained by population ageing. The increasing incidence in the elderly population was likely the consequence of an increasing precision in ALS diagnosis in the elderly since the increasing attention and care over time of neurologic elderly patients that likely concern elderly women more than previous time periods rather than better case ascertainment of diagnosed patients. The present findings do not support the role of specific environmental factors in ALS pathogenesis.

  14. Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Fogh, Isabella; Lin, Kuang; Tiloca, Cinzia; Rooney, James; Gellera, Cinzia; Diekstra, Frank P; Ratti, Antonia; Shatunov, Aleksey; van Es, Michael A; Proitsi, Petroula; Jones, Ashley; Sproviero, William; Chiò, Adriano; McLaughlin, Russell Lewis; Sorarù, Gianni; Corrado, Lucia; Stahl, Daniel; Del Bo, Roberto; Cereda, Cristina; Castellotti, Barbara; Glass, Jonathan D; Newhouse, Steven; Dobson, Richard; Smith, Bradley N; Topp, Simon; van Rheenen, Wouter; Meininger, Vincent; Melki, Judith; Morrison, Karen E; Shaw, Pamela J; Leigh, P Nigel; Andersen, Peter M; Comi, Giacomo P; Ticozzi, Nicola; Mazzini, Letizia; D'Alfonso, Sandra; Traynor, Bryan J; Van Damme, Philip; Robberecht, Wim; Brown, Robert H; Landers, John E; Hardiman, Orla; Lewis, Cathryn M; van den Berg, Leonard H; Shaw, Christopher E; Veldink, Jan H; Silani, Vincenzo; Al-Chalabi, Ammar; Powell, John

    2016-07-01

    Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. To identify gene variants influencing survival in ALS. This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10-9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10-8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10-9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10-8), corresponding to a 4-month reduction in survival compared with TT carriers. This GWAS robustly identified 2 loci at genome-wide levels of

  15. A Retrospective Study of the Characteristics and Clinical Significance of A-Waves in Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Jia Fang

    2017-09-01

    Full Text Available A-wave was observed in patients with motor neuron disease (1. However, data on the characteristics and clinical significance of A-waves in patients with amyotrophic lateral sclerosis (ALS have been scarce. The F-wave studies of 83 patients with ALS and 63 normal participants which were conducted previously at the Department of Neurology in Peking Union Medical College Hospital were retrospectively reviewed to determine the occurrence of A-waves in ALS. A-waves occurred more frequently in ALS patients than in normal controls. For the median and peroneal nerves, the frequencies of nerves with A-waves and frequencies of patients with A-waves were comparable between the ALS patients and normal controls. For the ulnar and tibial nerves, the frequencies of nerves with A-waves and frequencies of patients with A-waves were significantly increased in the ALS patients compared with those of the normal participants. Disease progression rate was slower in the ALS patients with A-waves (0.73 ± 0.99 than that in the ALS patients without A-waves (0.87 ± 0.55, P = 0.007. No correlations were found between the amplitudes of F-waves with A-waves and those of A-waves in the ulnar nerves (r = 0.423, P = 0.149. No correlations were found between the persistence of F-waves with A-waves and the persistence of A-waves in the ulnar nerves as well (r = 0.219, P = 0.473. The occurrence of A-waves may indicate dysfunction of lower motor neurons and possibly imply a relatively slower degenerative process.

  16. Neuroprotective Effect of Bexarotene in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Riancho, Javier; Ruiz-Soto, María; Berciano, María T.; Berciano, José; Lafarga, Miguel

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness and muscle atrophy related to the loss of upper and lower motor neurons (MNs) without a curative treatment. There is experimental evidence suggesting that retinoids may be involved in ALS pathogenesis. Bexarotene (Bxt) is a retinoid-X receptor agonist used in the treatment of cutaneous lymphoma with a favorable safety profile whose effects have been recently investigated in other neurodegenerative diseases. In this study, we analyze the potential therapeutic effect of Bxt in the SOD1G93A mouse model of ALS. Mice were treated with Bxt or vehicle five times per week from day 60 onward. Survival, weight, and neuromuscular function studies together with histological and biochemical analyses were performed. Bxt significantly delayed motor function deterioration, ameliorated the loss of body weight, and extended mice survival up to 30% of the symptomatic period. Histological analyses of the lumbosacral spinal cord revealed that Bxt markedly delayed the early motor-neuron degeneration occurring at presymptomatic stages in ALS-transgenic mice. Bxt treatment contributed to preserve the MN homeostasis in the SOD1G93A mice. Particularly, it reduced the neuronal loss and the chromatolytic response, induced nucleolar hypertrophy, decreased the formation of ubiquitylated inclusions, and modulated the lysosomal response. As an agonist of the retinoic-X receptor (RXR) pathway, Bxt notably increased the nuclear expression of the RXRα throughout transcriptionally active euchromatin domains. Bxt also contributed to protect the MN environment by reducing reactive astrogliosis and preserving perisomatic synapsis. Overall, these neuroprotective effects suggest that treatment with Bxt could be useful in ALS, particularly in those cases related to SOD1 mutations. PMID:26190974

  17. Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: a population-based study.

    Science.gov (United States)

    Chiò, Adriano; Calvo, Andrea; Bovio, Giacomo; Canosa, Antonio; Bertuzzo, Davide; Galmozzi, Francesco; Cugnasco, Paolo; Clerico, Marinella; De Mercanti, Stefania; Bersano, Enrica; Cammarosano, Stefania; Ilardi, Antonio; Manera, Umberto; Moglia, Cristina; Sideri, Riccardo; Marinou, Kalliopi; Bottacchi, Edo; Pisano, Fabrizio; Cantello, Roberto; Mazzini, Letizia; Mora, Gabriele

    2014-09-01

    There is an urgent need to identify reliable biomarkers of amyotrophic lateral sclerosis (ALS) progression for clinical practice and pharmacological trials. To correlate several hematological markers evaluated at diagnosis with ALS outcome in a population-based series of patients (discovery cohort) and replicate the findings in an independent validation cohort from an ALS tertiary center. The discovery cohort included 712 patients with ALS from the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis from January 1, 2007, to December 31, 2011. The validation cohort comprised 122 patients with ALS at different stages of disease consecutively seen at an ALS tertiary center between January 1, 2007, and January 1, 2009. The following hematological factors were investigated and correlated with survival: total leukocytes, neutrophils, lymphocytes, monocytes, glucose, creatinine, uric acid, albumin, bilirubin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatine kinase, thyroid-stimulating hormones, and erythrocyte sedimentation rate; all analyses were performed separately by sex. The patient of the validation cohort also underwent bioelectrical impedance analysis for the calculation of fat-free mass. Of the 712 patients in the examined period in Piemonte and Valle d'Aosta, 638 (89.6%) were included in the study. Only serum albumin (men: ≤ 4.3 vs >4.3 mg/dL, P 4.3 mg/dL, P creatinine levels (men: ≤ 0.82 vs >0.82 mg/dL, P = .004; women: ≤ 0.65 vs >0.05 mg/dL, P = .004) and lymphocyte count (men: ≤ 1700 vs >1700/μL, P = .04; women: ≤ 1700 vs >1700/μL, P = .02) were significantly associated with ALS outcome in both sexes with a dose-response effect (better survival with increasing levels). These findings were confirmed in the validation cohort. Multivariable analysis showed that serum albumin (men: hazard ratio [HR], 1.39; 95% CI, 1.05-1.90; P = .02; women: HR, 1.73; 95

  18. Characterization of Patients with Amyotrophic Lateral Sclerosis attending the Muscular Dystrophy Association-Supported Clinics in Puerto Rico.

    Science.gov (United States)

    Deliz, Brenda; Ramos, Kathya; Pérez, Cynthia M

    2018-03-01

    To evaluate the sociodemographic characteristics and clinical and functional profile of amyotrophic lateral sclerosis (ALS) patients evaluated at Puerto Rico's Muscular Dystrophy Association-supported (MDA) clinics. A retrospective review of 76 medical records of ALS patients evaluated at any of four MDA-sponsored clinics in Puerto Rico. The mean age of diagnosis was 57.4 ± 11.1 yrs. Most of the patients (52.3%) were women. The majority of the cases were sporadic (48.7%). Over 40% of the patients were diagnosed at one year or earlier. Patients with initial upper extremity involvement (63.2%) were diagnosed earlier (≤ 6 months) than any of the others. The most common presentation of the disease overall was lower extremity weakness (34.2%), which was followed by a bulbar presentation (31.6%). There was a marked difference between men and women in disease presentation, with bulbar involvement in 75% of the women. This study characterized a sample of ALS patients in Puerto Rico who are receiving services at the MDA-sponsored clinics. Puerto Rican patients have similarities with published data from the United States and other countries, including: sporadic pattern, initial symptoms in extremities, and time to diagnosis. Major differences are that the disease was more common in women than in men and that a higher than expected percentage of patients presented with bulbar onset. This may partly account for the overall predominance of the disease in women over men as found in our study, since the bulbar presentation has been reported to be more common in women. Studies with a greater number of patients are needed to determine whether our findings are reproducible. This study will serve as a basis for designing future analytic studies regarding etiology or the factors that might modulate disease progression.

  19. Mutations in the HFE gene and sporadic amyotrophic lateral sclerosis risk: a meta-analysis of observational studies

    Directory of Open Access Journals (Sweden)

    M. Li

    2014-03-01

    Full Text Available Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegenerative diseases. The H63D and C282Y polymorphisms in the HFE gene may be involved in the development of sporadic amyotrophic lateral sclerosis (ALS through the disruption of iron homeostasis. However, studies investigating the relationship between ALS and these two polymorphisms have yielded contradictory outcomes. We performed a meta-analysis to assess the roles of the H63D and C282Y polymorphisms of HFE in ALS susceptibility. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched to identify relevant studies. Strict selection criteria and exclusion criteria were applied. Odds ratios (ORs with 95% confidence intervals (CIs were used to assess the strength of associations. A fixed- or random-effect model was selected, depending on the results of the heterogeneity test. Fourteen studies were included in the meta-analysis (six studies with 1692 cases and 8359 controls for C282Y; 14 studies with 5849 cases and 13,710 controls for H63D. For the C282Y polymorphism, significant associations were observed in the allele model (Y vs C: OR=0.76, 95%CI=0.62-0.92, P=0.005 and the dominant model (YY+CY vs CC: OR=0.75, 95%CI=0.61-0.92, P=0.006. No associations were found for any genetic model for the H63D polymorphism. The C282Y polymorphism in HFE could be a potential protective factor for ALS in Caucasians. However, the H63D polymorphism does not appear to be associated with ALS.

  20. On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia.

    LENUS (Irish Health Repository)

    Geser, F

    2011-12-01

    Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) has been recognized as the major disease protein in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin positive, tau and α-synuclein negative inclusions (FTLD-U) and the transitional forms between these multisystem conditions. In order to develop TDP-43 into a successful ALS biomarker, the natural history of TDP-43 pathology needs to be characterized and the underlying pathophysiology established. Here we propose a spatial and temporal "two-axes" model of central nervous system vulnerability for TDP-43 linked degeneration and review recent studies on potential biomarkers related to pathological TDP-43 in the cerebrospinal fluid (CSF), blood, and skeletal muscle. The model includes the following two arms: Firstly, a "motor neuron disease" or "spinal cord\\/brainstem to motor cortex" axis (with degeneration possibly ascending from the lower motor neurons to the upper motor neurons); and secondly, a "dementia" or "corticoid\\/allocortex to neocortex" axis (with a probable spread of TDP-43 linked degeneration from the mediotemporal lobe to wider mesocortical and neocortical brain areas). At the cellular level, there is a gradual disappearance of normal TDP-43 in the nucleus in combination with the formation of pathological aggregates in the cell body and cellular processes, which can also be used to identify the stage of the disease process. Moreover, TDP-43 lesions in subpial\\/subependymal or perivascular localizations have been noted, and this might account for increased CSF and blood TDP-43 levels through mechanisms that remain to be elucidated.

  1. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)--revised report of an EFNS task force.

    Science.gov (United States)

    Andersen, Peter M; Abrahams, Sharon; Borasio, Gian D; de Carvalho, Mamede; Chio, Adriano; Van Damme, Philip; Hardiman, Orla; Kollewe, Katja; Morrison, Karen E; Petri, Susanne; Pradat, Pierre-Francois; Silani, Vincenzo; Tomik, Barbara; Wasner, Maria; Weber, Markus

    2012-03-01

    The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. To provide evidence-based or expert recommendations for the diagnosis and management of ALS based on a literature search and the consensus of an expert panel. All available medical reference systems were searched, and original papers, meta-analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus. Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non-invasive positive-pressure ventilation also improves survival and quality of life. Maintaining the patient's ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end-of-life care should be discussed early with the patient and carers, respecting the patient's social and cultural background. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.

  2. EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) - revised report of an EFNS task force.

    LENUS (Irish Health Repository)

    2012-02-01

    Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and management of ALS based on a literature search and the consensus of an expert panel. Methods: All available medical reference systems were searched, and original papers, meta-analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus. Recommendations: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives\\/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non-invasive positive-pressure ventilation also improves survival and quality of life. Maintaining the patient\\'s ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end-of-life care should be discussed early with the patient and carers, respecting the patient\\'s social and cultural background.

  3. Deleterious effects of lymphocytes at the early stage of neurodegeneration in an animal model of amyotrophic lateral sclerosis

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    Nakatsuji Yuji

    2011-02-01

    Full Text Available Abstract Background Non-neuronal cells, such as microglia and lymphocytes, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS. Previous studies have demonstrated neuroprotective effects of lymphocytes at the end stage of ALS, partly through induction of alternatively activated microglia (M2 microglia, which are neuroprotective. In this study, we investigated the role of lymphocytes in the early stage of the disease using an animal model of inherited ALS. Methods We established a transgenic mouse line overexpressing the familial ALS-associated G93A-SOD1 mutation (harboring a single amino acid substitution of glycine to alanine at codon 93 with depletion of the Rag2 gene (mSOD1/RAG2-/- mice, an animal model of inherited ALS lacking mature lymphocytes. Body weights, clinical scores and motor performance (hanging wire test of mSOD1/RAG2-/- mice were compared to those of mutant human SOD1 transgenic mice (mSOD1/RAG2+/+ mice. Activation of glial cells in the spinal cords of these mice was determined immunohistochemically, and the expression of mRNA for various inflammatory and anti-inflammatory molecules was evaluated. Results Clinical onset in mSOD1/RAG2-/- mice was significantly delayed, and the number of lectin-positive cells in spinal cord was increased at the early stage of disease when compared to mSOD1/RAG2+/+ mice. Quantitative RT-PCR confirmed that mRNA for Ym1, an M2 microglial-related molecule, was significantly increased in mSOD1/RAG2-/- mouse spinal cords at the early disease stage. Conclusions Compared with mSOD1/RAG2+/+ mice, mSOD1/RAG2-/- mice displayed delayed onset and increased M2 microglial activation at the early stage of disease. Thus, lymphocytes at the early pathological phase of ALS display a deleterious effect via inhibition of M2 microglial activation.

  4. Survival in amyotrophic lateral sclerosis with home mechanical ventilation: the impact of systematic respiratory assessment and bulbar involvement.

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    Farrero, Eva; Prats, Enric; Povedano, Mónica; Martinez-Matos, J Antonio; Manresa, Frederic; Escarrabill, Joan

    2005-06-01

    To analyze (1) the impact of a protocol of early respiratory evaluation of the indications for home mechanical ventilation (HMV) in patients with amyotrophic lateral sclerosis (ALS), and (2) the effects of the protocol and of bulbar involvement on the survival of patients receiving noninvasive ventilation (NIV). Retrospective study in a tertiary care referral center. HMV was indicated in 86 patients with ALS, with 22 patients (25%) presenting with intolerance to treatment associated with bulbar involvement. Treatment with HMV had been initiated in 15 of 64 patients prior to initiating the protocol (group A) and in the remaining 49 patients after protocol initiation (group B). In group A, the majority of patients began treatment with HMV during an acute episode requiring ICU admission (p = 0.001) and tracheal ventilation (p = 0.025), with a lower percentage of patients beginning HMV treatment without respiratory insufficiency (p = 0.013). No significant differences in survival rates were found between groups A and B among patients treated with NIV. Greater survival was observed in group B (p = 0.03) when patients with bulbar involvement were excluded (96%). Patients without bulbar involvement at the start of therapy with NIV presented a significantly better survival rate (p = 0.03). Multivariate analysis showed bulbar involvement to be an independent prognostic factor for survival (relative risk, 1.6; 95% confidence interval, 1.01 to 2.54; p = 0.04). No significant differences in survival were observed between patients with bulbar involvement following treatment with NIV and those with intolerance, except for the subgroup of patients who began NIV treatment with hypercapnia (p = 0.0002). Early systematic respiratory evaluation in patients with ALS is necessary to improve the results of HMV. Further studies are required to confirm the benefits of NIV treatment in patients with bulbar involvement, especially in the early stages.

  5. Neural induction with neurogenin 1 enhances the therapeutic potential of mesenchymal stem cells in an amyotrophic lateral sclerosis mouse model.

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    Chan-Il, Choi; Young-Don, Lee; Heejaung, Kim; Kim, Seung Hyun; Suh-Kim, Haeyoung; Kim, Sung-Soo

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in the central nervous system (CNS). In the absence of effective drug treatments for ALS, stem cell treatment has emerged as a candidate therapy for this disease. To date, however, there is no consensus protocol that stipulates stem cell types, transplantation timing, or frequency. Using an ALS mouse model carrying a high copy number of a mutant human superoxide dismutase-1 (SOD1)(G93A) transgene, we investigated the effect of neural induction on the innate therapeutic potential of mesenchymal stem cells (MSCs) in relation to preclinical transplantation parameters. In our study, the expression of monocyte chemoattractant protein-1 (MCP-1) was elevated in the ALS mouse spinal cord. Neural induction of MSCs with neurogenin 1 (Ngn1) upregulated the expression level of the MCP-1 receptor, CCR2, and enhanced the migration activity toward MCP-1 in vitro. Ngn1-expressing MSCs (MSCs-Ngn1) showed a corresponding increase in tropism to the CNS after systemic transplantation in ALS mice. Notably, MSCs-Ngn1 delayed disease onset if transplanted during preonset ages,whereas unprocessed MSCs failed to do so. If transplanted near the onset ages, a single treatment with MSCs-Ngn1 was sufficient to enhance motor functions during the symptomatic period (15–17 weeks), whereas unprocessed MSCs required repeated transplantation to achieve similar levels of motor function improvement. Our data indicate that systemically transplanted MSCs-Ngn1 can migrate to the CNS and exert beneficial effects on host neural cells for an extended period of time through paracrine functions, suggesting a potential benefit of neural induction of transplanted MSCs in long-term treatment of ALS.

  6. ERBB4 Mutations that Disrupt the Neuregulin-ErbB4 Pathway Cause Amyotrophic Lateral Sclerosis Type 19

    Science.gov (United States)

    Takahashi, Yuji; Fukuda, Yoko; Yoshimura, Jun; Toyoda, Atsushi; Kurppa, Kari; Moritoyo, Hiroyoko; Belzil, Veronique V.; Dion, Patrick A.; Higasa, Koichiro; Doi, Koichiro; Ishiura, Hiroyuki; Mitsui, Jun; Date, Hidetoshi; Ahsan, Budrul; Matsukawa, Takashi; Ichikawa, Yaeko; Moritoyo, Takashi; Ikoma, Mayumi; Hashimoto, Tsukasa; Kimura, Fumiharu; Murayama, Shigeo; Onodera, Osamu; Nishizawa, Masatoyo; Yoshida, Mari; Atsuta, Naoki; Sobue, Gen; Fifita, Jennifer A.; Williams, Kelly L.; Blair, Ian P.; Nicholson, Garth A.; Gonzalez-Perez, Paloma; Brown, Robert H.; Nomoto, Masahiro; Elenius, Klaus; Rouleau, Guy A.; Fujiyama, Asao; Morishita, Shinichi; Goto, Jun; Tsuji, Shoji

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3–5 years from onset. Familial ALS (FALS) comprises 5%–10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions. PMID:24119685

  7. Monitoring CSF proteome alterations in amyotrophic lateral sclerosis: obstacles and perspectives in translating a novel marker panel to the clinic.

    Directory of Open Access Journals (Sweden)

    Nils von Neuhoff

    Full Text Available BACKGROUND: Amyotrophic lateral sclerosis (ALS is a fatal disorder of the motor neuron system with poor prognosis and marginal therapeutic options. Current clinical diagnostic criteria are based on electrophysiological examination and exclusion of other ALS-mimicking conditions. Neuroprotective treatments are, however, most promising in early disease stages. Identification of disease-specific CSF biomarkers and associated biochemical pathways is therefore most relevant to monitor disease progression, response to neuroprotective agents and to enable early inclusion of patients into clinical trials. METHODS AND FINDINGS: CSF from 35 patients with ALS diagnosed according to the revised El Escorial criteria and 23 age-matched controls was processed using paramagnetic bead chromatography for protein isolation and subsequently analyzed by MALDI-TOF mass spectrometry. CSF protein profiles were integrated into a Random Forest model constructed from 153 mass peaks. After reducing this peak set to the top 25%, a classifier was built which enabled prediction of ALS with high accuracy, sensitivity and specificity. Further analysis of the identified peptides resulted in a panel of five highly sensitive ALS biomarkers. Upregulation of secreted phosphoprotein 1 in ALS-CSF samples was confirmed by univariate analysis of ELISA and mass spectrometry data. Further quantitative validation of the five biomarkers was achieved in an 80-plex Multiple Reaction Monitoring mass spectrometry assay. CONCLUSIONS: ALS classification based on the CSF biomarker panel proposed in this study could become a valuable predictive tool for early clinical risk stratification. Of the numerous CSF proteins identified, many have putative roles in ALS-related metabolic processes, particularly in chromogranin-mediated secretion signaling pathways. While a stand-alone clinical application of this classifier will only be possible after further validation and a multicenter trial, it could be

  8. Is the effect of non-invasive ventilation on survival in amyotrophic lateral sclerosis age-dependent?

    Science.gov (United States)

    Siirala, Waltteri; Aantaa, Riku; Olkkola, Klaus T; Saaresranta, Tarja; Vuori, Arno

    2013-01-01

    Hypoventilation due to respiratory muscle atrophy is the most common cause of death as a result of amyotrophic lateral sclerosis (ALS). Patients aged over 65 years and presenting bulbar symptoms are likely to have a poorer prognosis. The aim of the study was to assess the possible impact of age and treatment with non-invasive ventilation (NIV) on survival in ALS. Based on evidence from earlier studies, it was hypothesized that NIV increases rates of survival regardless of age. Eighty-four patients diagnosed with ALS were followed up on from January 2001 to June 2012. These patients were retrospectively divided into two groups according to their age at the time of diagnosis: Group 1 comprised patients aged ≤ 65 years while Group 2 comprised those aged > 65 years. Each group included 42 patients. NIV was tolerated by 23 patients in Group 1 and 18 patients in Group 2. Survival was measured in months from the date of diagnosis. The median age in Group 1 was 59 years (range 49 - 65) and 76 years in Group 2 (range 66 - 85). Among patients in Group 1 there was no difference in probability of survival between the NIV users and non-users (Hazard Ratio = 0.88, 95% CI 0.44 - 1.77, p = 0.7). NIV users in Group 2 survived longer than those following conventional treatment (Hazard Ratio = 0.25, CI 95% 0.11 - 0.55, p NIV had a 4-fold higher risk for death compared with NIV users. This retrospective study found that NIV use was associated with improved survival outcomes in ALS patients older than 65 years. Further studies in larger patient populations are warranted to determine which factors modify survival outcomes in ALS.

  9. Life course body mass index and risk and prognosis of amyotrophic lateral sclerosis: results from the ALS registry Swabia.

    Science.gov (United States)

    Peter, Raphael Simon; Rosenbohm, Angela; Dupuis, Luc; Brehme, Torben; Kassubek, Jan; Rothenbacher, Dietrich; Nagel, Gabriele; Ludolph, Albert Christian

    2017-10-01

    Weight loss appears as a strong predictor of survival of patients with amyotrophic lateral sclerosis, yet no data are currently available to describe the life course history of pre-diagnostic body mass index (BMI) in these patients. 393 ALS cases (mean age: 65.8 years, 57.3% men) and 791 controls matched by age and sex from a population-based case-control study of the ALS Registry Swabia were analyzed. Differences of BMI change in cases and controls over time were modeled using a multilevel additive model. In addition, survival in ALS cases by BMI change was modeled using an accelerated failure time model adjusted for prognostic factors. In ALS cases, BMI was consistently higher than in controls in the 20-70 years before the interview. Conditional logistic regression revealed an odds ratio of 1.05 (95% confidence interval (CI) 1.00-1.11, p = 0.041) per 1 kg/m 2 higher BMI 35-45 years before interview. However, a sharp decrease was evident in the BMI of ALS cases about 10 years before disease onset. Moreover, weight loss was strongly associated with shorter survival in ALS patients. Illustrating this, patients with stable weight showed a median survival time of 22.1 (95%-CI 19.2-25.0) months, as compared to 13.4 (95%-CI 10.5-16.3) months for patients with weight loss of 2.5 kg/m 2 over the last 3 months before the interview. Thus, alterations in body weight are present in ALS patients already decades before clinical manifestation of ALS, while weight loss precedes motor symptoms of several years and is associated with poor prognosis.

  10. The corticospinal tract lesion of amyotrophic lateral sclerosis. Magnetic resonance imaging of the spinal cord

    International Nuclear Information System (INIS)

    Terao, Shin-ichi; Sobue, Gen; Mitsuma, Terunori; Yasuda, Takeshi; Kachi, Teruhiko.

    1994-01-01

    Magnetic resonance imaging by gradient echo method demonstrated lesions of the lateral corticospinal tract at cervical cord levels in three ALS patients. Patient 1 was a 43-year-old woman with common from of ALS. She developed right-side predominant pyramidal signs, and right-side predominant prolongation of central motor conduction time. MRI showed hypersignal intensity areas in the dorsal region of the lateral column at the 4th and 5th cervical segments with right-side predominacy. Patient 2 was a 65-year-old man with pseudopolyneuritic from of ALS, who showed lower motor neuron signs without a pyramidal sign. MRI of the 3rd and 4th cervical cord segments demonstrated bilateral hypersignal intensity areas in the dorsal part of the lateral column. Patient 3 was a 62-year-old man with common form of ALS, who showed marked bilateral pyramidal signs with Babinski's sign. MRI of the 5th cervical spinal cord segment demonstrated bilateral hypersignal intensity areas in the dorsolateral column. MR images of the spinal cord thus obtained corresponded well to the postmortem confirmed degeneration of the spinal corticospinal tract. MRI of the spinal cord performed by gradient echo method would provide additional information on the upper motor neuron involvement in ALS. (author)

  11. The corticospinal tract lesion of amyotrophic lateral sclerosis. Magnetic resonance imaging of the spinal cord

    Energy Technology Data Exchange (ETDEWEB)

    Terao, Shin-ichi; Sobue, Gen; Mitsuma, Terunori (Aichi Medical Univ., Nagakute (Japan)); Yasuda, Takeshi; Kachi, Teruhiko

    1994-09-01

    Magnetic resonance imaging by gradient echo method demonstrated lesions of the lateral corticospinal tract at cervical cord levels in three ALS patients. Patient 1 was a 43-year-old woman with common from of ALS. She developed right-side predominant pyramidal signs, and right-side predominant prolongation of central motor conduction time. MRI showed hypersignal intensity areas in the dorsal region of the lateral column at the 4th and 5th cervical segments with right-side predominacy. Patient 2 was a 65-year-old man with pseudopolyneuritic from of ALS, who showed lower motor neuron signs without a pyramidal sign. MRI of the 3rd and 4th cervical cord segments demonstrated bilateral hypersignal intensity areas in the dorsal part of the lateral column. Patient 3 was a 62-year-old man with common form of ALS, who showed marked bilateral pyramidal signs with Babinski's sign. MRI of the 5th cervical spinal cord segment demonstrated bilateral hypersignal intensity areas in the dorsolateral column. MR images of the spinal cord thus obtained corresponded well to the postmortem confirmed degeneration of the spinal corticospinal tract. MRI of the spinal cord performed by gradient echo method would provide additional information on the upper motor neuron involvement in ALS. (author).

  12. Investigating the neuroanatomical substrate of pathological laughing and crying in amyotrophic lateral sclerosis with multimodal neuroimaging techniques.

    Science.gov (United States)

    Christidi, Foteini; Karavasilis, Efstratios; Ferentinos, Panagiotis; Xirou, Sophia; Velonakis, Georgios; Rentzos, Michalis; Zouvelou, Vasiliki; Zalonis, Ioannis; Efstathopoulos, Efstathios; Kelekis, Nikolaos; Evdokimidis, Ioannis

    2018-02-01

    Pathological laughing and crying (PLC) is common in several neurological and psychiatric diseases and is associated with a distributed network involving the frontal cortex, the brainstem and cortico-pontine-cerebellar circuits. By applying multimodal neuroimaging approach, we examined the neuroanatomical substrate of PLC in a sample of patients with amyotrophic lateral sclerosis (ALS). We studied 56 non-demented ALS patients and 25 healthy controls (HC). PLC was measured in ALS using the Center of Neurologic Study Lability Scale (CNS-LS; cutoff score: 13). All participants underwent 3D-T1-weighted and 30-directional diffusion-weighted imaging at 3T. Voxel-based morphometry and tract-based spatial-statistics analysis was used to examine gray matter (GM) and white matter (WM) differences between ALS patients with and without PLC (ALS-PLC and ALS-nonPLC, respectively). Comparisons were restricted to regions with detected differences between ALS and HC, controlling for age, gender, total intracranial volume and depressive symptoms. In regions with significant differences between ALS and HC, ALS-PLC patients showed decreased GM volume in left orbitofrontal cortex, frontal operculum, and putamen and bilateral frontal poles, compared to ALS-nonPLC. They also had decreased fractional anisotropy in left cingulum bundle and posterior corona radiata. WM abnormalities were additionally detected in WM associative and ponto-cerebellar tracts (using a more liberal threshold). PLC in ALS is driven by both GM and WM abnormalities which highlight the role of circuits rather than isolated centers in the emergence of this condition. ALS is suggested as a useful natural experimental model to study PLC.

  13. A systematic review of the effect of moderate intensity exercise on function and disease progression in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Lui, Andrew J; Byl, Nancy N

    2009-06-01

    Amyotrophic lateral sclerosis (ALS) is an idiopathic disease of adults affecting upper and lower motor neurons. In one to four years, progressive weakness, spasticity, and respiratory insufficiency compromise independence and survival. Current medical treatment is limited to medication and supportive care. The benefit and harm of moderate physical exercise are controversial. This review examined current research related to moderate exercise for maintaining independence without accelerating disease progression in persons with ALS. An evidence-based search was conducted using keywords alone and in combination (ALS, exercise, Lou Gehrig's disease, physical therapy) to search PubMed, PEDro, Hooked on Evidence, Ovid, and Cochrane databases. Human and animal models were included and graded on level of evidence and strength of recommendations for developing guidelines to practice. A secondary reviewer evaluated all selected studies, and statistics were calculated. The search yielded the following nine studies: four small clinical studies, one clinical systematic review, and four randomized, controlled trials based on animal models. In human studies, there were small to moderate effect sizes supporting the benefit of moderate exercise in persons with early-stage ALS, with no adverse affects on disease progression or survival time. In transgenic mice with superoxide dismutase-1 ALS, moderate exercise most often had a moderate effect size for increasing life span. Large randomized clinical trials are needed to develop specific exercise guidelines. However, evidence suggests that moderate exercise is not associated with adverse outcomes in persons with early-stage ALS. Moderate exercise programs can be safely adapted to abilities, interests, specific response to exercise, accessibility, and family support.

  14. Severe brain atrophy after long-term survival seen in siblings with familial amyotrophic lateral sclerosis and a mutation in the optineurin gene: a case series

    Directory of Open Access Journals (Sweden)

    Ueno Hiroki

    2011-12-01

    Full Text Available Abstract Introduction Previous studies have shown widespread multisystem degeneration in patients with sporadic amyotrophic lateral sclerosis who develop a total locked-in state and survive under mechanical ventilation for a prolonged period of time. However, the disease progressions reported in these studies were several years after disease onset. There have been no reports of long-term follow-up with brain imaging of patients with familial amyotrophic lateral sclerosis at an advanced stage of the disease. We report the cases of siblings with amyotrophic lateral sclerosis with homozygous deletions of the exon 5 mutation of the gene encoding optineurin, in whom brain computed tomography scans were followed up for more than 20 years. Case presentation The patients were a Japanese brother and sister. The elder sister was 33 years of age at the onset of disease, which began with muscle weakness of her left lower limb. Two years later she required mechanical ventilation. She became bedridden at the age of 34, and died at the age of 57. A computed tomography scan of her brain at the age of 36 revealed no abnormality. Atrophy of her brain gradually progressed. Ten years after the onset of mechanical ventilation, atrophy of her whole brain, including the cerebral cortex, brain stem and cerebellum, markedly progressed. Her younger brother was 36 years of age at the onset of disease, which presented as muscle weakness of his left upper limb. One year later, he showed dysphagia and dysarthria, and tracheostomy ventilation was performed. He became bedridden at the age of 37 and died at the age of 55. There were no abnormal intracranial findings on brain computed tomography scans obtained at the age of 37 years. At the age of 48 years, computed tomography scans showed marked brain atrophy with ventricular dilatation. Subsequently, atrophy of the whole brain rapidly progressed as in his elder sister. Conclusion We conclude that a homozygous deletion

  15. 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

  16. A Potential Biomarker in Amyotrophic Lateral Sclerosis: Can Assessment of Brain Iron Deposition with SWI and Corticospinal Tract Degeneration with DTI Help?

    Science.gov (United States)

    Sheelakumari, R; Madhusoodanan, M; Radhakrishnan, A; Ranjith, G; Thomas, B

    2016-02-01

    Iron-mediated oxidative stress plays a pivotal role in the pathogenesis of amyotrophic lateral sclerosis. This study aimed to assess iron deposition qualitatively and quantitatively by using SWI and microstructural changes in the corticospinal tract by using DTI in patients with amyotrophic lateral sclerosis. Seventeen patients with amyotrophic lateral sclerosis and 15 age- and sex-matched controls underwent brain MR imaging with SWI and DTI. SWI was analyzed for both signal-intensity scoring and quantitative estimation of iron deposition in the anterior and posterior banks of the motor and sensory cortices and deep gray nuclei. The diffusion measurements along the corticospinal tract at the level of pons and medulla were obtained by ROI analysis. Patients with amyotrophic lateral sclerosis showed reduced signal-intensity grades in the posterior bank of the motor cortex bilaterally. Quantitative analysis confirmed significantly higher iron content in the posterior bank of the motor cortex in patients with amyotrophic lateral sclerosis. In contrast, no significant differences were noted for the anterior bank of the motor cortex, anterior and posterior banks of the sensory cortex, and deep nuclei. Receiver operating characteristic comparison showed a cutoff of 35μg Fe/g of tissue with an area under the curve of 0.78 (P = .008) for the posterior bank of the motor cortex in discriminating patients with amyotrophic lateral sclerosis from controls. Fractional anisotropy was lower in the pyramidal tracts of patients with amyotrophic lateral sclerosis at the pons and medulla on either side, along with higher directionally averaged mean diffusivity values. The combination of SWI and DTI revealed an area under the curve of 0.784 for differentiating patients with amyotrophic lateral sclerosis from controls. Measurements of motor cortex iron deposition and diffusion tensor parameters of the corticospinal tract may be useful biomarkers for the diagnosis of clinically suspected

  17. sup 26 Al tracer experiment by accelerator mass spectrometry and its application to the studies for amyotrophic lateral sclerosis and Alzheimer's disease, 1

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Koichi (Tokyo Univ. (Japan). Research Center for Nuclear Science and Technology); Yumoto, Sakae; Nagai, Hisao; Hosoyama, Yoshiyuki; Imamura, Mineo; Masuzawa, Shin-ichirou; Koizumi, Yoshinobu; Yamashita, Hiroshi

    1990-12-01

    Accelerator mass spectrometry (AMS) was applied for {sup 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 {sup 26}Al as a tracer. When {sup 26}Al was intraperitoneally injected into rats, a considerable amount of {sup 26}Al was incorporated into the cerebrum after 5-35 days of the injection. (author).

  18. The combined use of conventional MRI and MR spectroscopic imaging increases the diagnostic accuracy in amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Cervo, Amedeo [Department of Advanced Biomedical Sciences, University “Federico II”, Naples (Italy); Cocozza, Sirio, E-mail: siriococozza@hotmail.it [Department of Advanced Biomedical Sciences, University “Federico II”, Naples (Italy); Saccà, Francesco [Department of Neurosciences, Reproductive Sciences and Odontostomatology, University “Federico II”, Naples (Italy); Giorgio, Sara M.d.A. [Department of Advanced Biomedical Sciences, University “Federico II”, Naples (Italy); Morra, Vincenzo Brescia [Department of Neurosciences, Reproductive Sciences and Odontostomatology, University “Federico II”, Naples (Italy); Tedeschi, Enrico [Department of Advanced Biomedical Sciences, University “Federico II”, Naples (Italy); Marsili, Angela; Vacca, Giovanni [Department of Neurosciences, Reproductive Sciences and Odontostomatology, University “Federico II”, Naples (Italy); Palma, Vincenzo [U.O.C. Neurofisiopatologia, PO S. Gennaro ASL Napoli 1, Naples (Italy); Brunetti, Arturo [Department of Advanced Biomedical Sciences, University “Federico II”, Naples (Italy); Quarantelli, Mario [Biostructure and Bioimaging Institute, National Research Council, Naples (Italy)

    2015-01-15

    Highlights: • We assessed in ALS the diagnostic accuracy of MRI signal and MRS data used alone and in combination. • We found that T2-hypointensity and NAA decrease in motor cortex are two independent phenomena. • These two variables taken alone do not provide acceptable diagnostic accuracy in ALS. • The same variables, when used in combination, improve the diagnostic accuracy of MRI in ALS. - Abstract: Purpose: We aimed to assess, in amyotrophic lateral sclerosis (ALS), the diagnostic accuracy of the combined use of conventional MRI signal changes (namely, hypointensity of the precentral cortex and hyperintensity of the corticospinal tracts on T2-weighted images), and N-Acetyl-Aspartate (NAA) reduction in the motor cortex at Magnetic Resonance Spectroscopy (MRS), which are affected by limited diagnostic accuracy when used separately. Methods: T2-hypointensity and NAA/(Choline + Creatine) ratio of the precentral gyrus and T2-hyperintensity of the corticospinal tracts were measured in 84 ALS patients and 28 healthy controls, using a Region-of-Interest approach. Sensitivity and specificity values were calculated using Fisher stepwise discriminant analysis, and cross-validated using the leave-one-out method. Results: Precentral gyrus T2 signal intensity (p < 10{sup −4}) and NAA peak (p < 10{sup −6}) were significantly reduced in patients, and their values did not correlate significantly to each other both in patients and controls, while no significant differences were obtained in terms of T2-hyperintensity of the corticospinal tract. Sensitivity and specificity of the two discriminant variables, taken alone, were 71.4% and 75.0%, for NAA peak, and 63.1% and 71.4% for T2-hypointensity, respectively. When using these two variables in combination, a significant increase in sensitivity (78.6%) and specificity (82.1%) was achieved. Conclusions: Precentral gyrus T2-hypointensity and NAA peak are not significantly correlated in ALS patients, suggesting that they

  19. The combined use of conventional MRI and MR spectroscopic imaging increases the diagnostic accuracy in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Cervo, Amedeo; Cocozza, Sirio; Saccà, Francesco; Giorgio, Sara M.d.A.; Morra, Vincenzo Brescia; Tedeschi, Enrico; Marsili, Angela; Vacca, Giovanni; Palma, Vincenzo; Brunetti, Arturo; Quarantelli, Mario

    2015-01-01

    Highlights: • We assessed in ALS the diagnostic accuracy of MRI signal and MRS data used alone and in combination. • We found that T2-hypointensity and NAA decrease in motor cortex are two independent phenomena. • These two variables taken alone do not provide acceptable diagnostic accuracy in ALS. • The same variables, when used in combination, improve the diagnostic accuracy of MRI in ALS. - Abstract: Purpose: We aimed to assess, in amyotrophic lateral sclerosis (ALS), the diagnostic accuracy of the combined use of conventional MRI signal changes (namely, hypointensity of the precentral cortex and hyperintensity of the corticospinal tracts on T2-weighted images), and N-Acetyl-Aspartate (NAA) reduction in the motor cortex at Magnetic Resonance Spectroscopy (MRS), which are affected by limited diagnostic accuracy when used separately. Methods: T2-hypointensity and NAA/(Choline + Creatine) ratio of the precentral gyrus and T2-hyperintensity of the corticospinal tracts were measured in 84 ALS patients and 28 healthy controls, using a Region-of-Interest approach. Sensitivity and specificity values were calculated using Fisher stepwise discriminant analysis, and cross-validated using the leave-one-out method. Results: Precentral gyrus T2 signal intensity (p < 10 −4 ) and NAA peak (p < 10 −6 ) were significantly reduced in patients, and their values did not correlate significantly to each other both in patients and controls, while no significant differences were obtained in terms of T2-hyperintensity of the corticospinal tract. Sensitivity and specificity of the two discriminant variables, taken alone, were 71.4% and 75.0%, for NAA peak, and 63.1% and 71.4% for T2-hypointensity, respectively. When using these two variables in combination, a significant increase in sensitivity (78.6%) and specificity (82.1%) was achieved. Conclusions: Precentral gyrus T2-hypointensity and NAA peak are not significantly correlated in ALS patients, suggesting that they reflect

  20. Blood oxygenation level dependent functional MRI study on the changes of motor cortex in patients with amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Han Jing; Ma Lin; Lou Xin; Yu Shengyuan; Li Dejun

    2008-01-01

    Objective: To study the changes of motor cortex in patients with amyotrophic lateral sclerosis (ALS) while executing sequential finger tapping movement by using blood oxygenation level dependent (BOLD) functional MRI. Methods: Fifteen patients with definite or probable ALS and 15 age and gender matched normal controls were enrolled in the BOLD study, and all the subjects were right-handed with no other diseases or any recent medication history. A 3.0 T MR scanner' was employed and gradient echo EPI (GRE-EPI)sequence was used to acquire the functional images. Subjects executed sequential finger tapping movement at a frequency of 1-2 Hz during a block design task. fMRI data were analyzed by using statistical parametric mapping (SPM) 2. Volume of activated brain areas was compared with the use of a Student's t-test. Results: Bilateral primary sensorimotor cortex (PSM), bilateral posterior aspect of premotor area (PA), bilateral supplementary motor area (SMA), contralateral inferior lateral premotor area (ILPA), bilateral parietal region (PAR), and ipsilateral cerebellum showed activation in both ALS patients and normal controls when executing the same motor task. The activation areas in bilateral PSM and bilateral posterior aspect of PA ( right hand ipsilateral activation: ALS (924.5±141.1) mm 3 , control (829.9± 98.4) mm 3 , P=0.05; right hand contralateral activation: ALS (9143.8±702.8) mm 3 , control (8638.8±506.4) mm 3 P 3 , control (902.5±3 184.2)mm , P 3 , control (5934.6±616.4) mm 3 , P 3 , control (4710.7±416.3) mm 3 , P 3 , control (3688.9±672.3) mm 3 , P 3 , control (254.3±84.4) mm 3 , P 3 , control (1689.0±719.6) mm 3 , P<0.05) were significantly larger in ALS patients than in normal controls. Extra activation areas including ipsilateral ILPA, contralateral cerebellum and bilateral posterior limb of internal capsule were only detected in ALS patients. Conclusions: Similar activation areas were seen in both groups while executing the same motor

  1. Development of a Smartphone App for a Genetics Website: The Amyotrophic Lateral Sclerosis Online Genetics Database (ALSoD).

    Science.gov (United States)

    Abel, Olubunmi; Shatunov, Aleksey; Jones, Ashley R; Andersen, Peter M; Powell, John F; Al-Chalabi, Ammar

    2013-09-04

    The ALS Online Genetics Database (ALSoD) website holds mutation, geographical, and phenotype data on genes implicated in amyotrophic lateral sclerosis (ALS) and links to bioinformatics resources, publications, and tools for analysis. On average, there are 300 unique visits per day, suggesting a high demand from the research community. To enable wider access, we developed a mobile-friendly version of the website and a smartphone app. We sought to compare data traffic before and after implementation of a mobile version of the website to assess utility. We identified the most frequently viewed pages using Google Analytics and our in-house analytic monitoring. For these, we optimized the content layout of the screen, reduced image sizes, and summarized available information. We used the Microsoft .NET framework mobile detection property (HttpRequest.IsMobileDevice in the Request.Browser object in conjunction with HttpRequest.UserAgent), which returns a true value if the browser is a recognized mobile device. For app development, we used the Eclipse integrated development environment with Android plug-ins. We wrapped the mobile website version with the WebView object in Android. Simulators were downloaded to test and debug the applications. The website automatically detects access from a mobile phone and redirects pages to fit the smaller screen. Because the amount of data stored on ALSoD is very large, the available information for display using smartphone access is deliberately restricted to improve usability. Visits to the website increased from 2231 to 2820, yielding a 26% increase from the pre-mobile to post-mobile period and an increase from 103 to 340 visits (230%) using mobile devices (including tablets). The smartphone app is currently available on BlackBerry and Android devices and will be available shortly on iOS as well. Further development of the ALSoD website has allowed access through smartphones and tablets, either through the website or directly through

  2. On the Relationship Between Attention Processing and P300-Based Brain Computer Interface Control in Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Angela Riccio

    2018-05-01

    Full Text Available Our objective was to investigate the capacity to control a P3-based brain-computer interface (BCI device for communication and its related (temporal attention processing in a sample of amyotrophic lateral sclerosis (ALS patients with respect to healthy subjects. The ultimate goal was to corroborate the role of cognitive mechanisms in event-related potential (ERP-based BCI control in ALS patients. Furthermore, the possible differences in such attentional mechanisms between the two groups were investigated in order to unveil possible alterations associated with the ALS condition. Thirteen ALS patients and 13 healthy volunteers matched for age and years of education underwent a P3-speller BCI task and a rapid serial visual presentation (RSVP task. The RSVP task was performed by participants in order to screen their temporal pattern of attentional resource allocation, namely: (i the temporal attentional filtering capacity (scored as T1%; and (ii the capability to adequately update the attentive filter in the temporal dynamics of the attentional selection (scored as T2%. For the P3-speller BCI task, the online accuracy and information transfer rate (ITR were obtained. Centroid Latency and Mean Amplitude of N200 and P300 were also obtained. No significant differences emerged between ALS patients and Controls with regards to online accuracy (p = 0.13. Differently, the performance in controlling the P3-speller expressed as ITR values (calculated offline were compromised in ALS patients (p < 0.05, with a delay in the latency of P3 when processing BCI stimuli as compared with Control group (p < 0.01. Furthermore, the temporal aspect of attentional filtering which was related to BCI control (r = 0.51; p < 0.05 and to the P3 wave amplitude (r = 0.63; p < 0.05 was also altered in ALS patients (p = 0.01. These findings ground the knowledge required to develop sensible classes of BCI specifically designed by taking into account the influence of the cognitive

  3. [Physiological parameters of breathing and the impact of non-invasive ventilation (NIV) on patients with amyotrophic lateral sclerosis (ALS)].

    Science.gov (United States)

    Czudaj, K-P; Suchi, S; Schönhofer, B

    2009-12-01

    Amyotrophic lateral sclerosis (ALS), as a consequence of the progressive failure of respiratory muscles, often causes chronic ventilatory failure (CVF), indicated by hypercapnia. This study analyses the physiological parameters of breathing in patients with ALS over time and the variables which influence survival time. In this observational study we analysed the data of physiological parameters (respiratory function, blood gas levels and breathing during sleep), as well as survival rate (according to Kaplan-Meier) of all 85 ALS patients who stayed in our hospital during the period of 1st January 2003 until 31st December 2007. After ALS had been diagnosed, all patients ran through standardised pneumological diagnostics during the observation period, this procedure was repeated every 3-6 months. If hypercapnia (carbon dioxide tension pCO(2) > 45 mm Hg) was detected, non-invasive ventilation (NIV) was indicated and offered to the respective patients. In the course of the observation, the parameters of respiratory function IVC (inspiratory vital capacity) and FEV1 (forced expiratory volume after 1 second) have shown a significant reduction by 14-15% per year. Half of the patients died within 3.1 years after ALS had been diagnosed. IVC and FEV1 had no impact on the survival time. In contrast, pCO(2) correlates negatively with the survival time. The period between diagnosis of ALS and manifestation of hypercapnia is about 1.9 +/- 2.4 years. In spite of a clear indication, some of the patients did not comply with NIV or did not accept it (19 patients, 22%). Twenty-eight patients (33%) started NIV with a good compliance. The survival rate of patients with NIV was 1.27 years on average--after the initial measurement of hypercapnia. The survival time of hypercapnic patients without NIV was only 0.12 years. Hypercapnia has a significant impact on the prognosis for ALS patients. In the case of CVF (hypercapnia), the survival time of ALS patients is significantly reduced. NIV

  4. Item response theory analysis of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised in the Pooled Resource Open-Access ALS Clinical Trials Database.

    Science.gov (United States)

    Bacci, Elizabeth D; Staniewska, Dorota; Coyne, Karin S; Boyer, Stacey; White, Leigh Ann; Zach, Neta; Cedarbaum, Jesse M

    2016-01-01

    Our objective was to examine dimensionality and item-level performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) across time using classical and modern test theory approaches. Confirmatory factor analysis (CFA) and Item Response Theory (IRT) analyses were conducted using data from patients with amyotrophic lateral sclerosis (ALS) Pooled Resources Open-Access ALS Clinical Trials (PRO-ACT) database with complete ALSFRS-R data (n = 888) at three time-points (Time 0, Time 1 (6-months), Time 2 (1-year)). Results demonstrated that in this population of 888 patients, mean age was 54.6 years, 64.4% were male, and 93.7% were Caucasian. The CFA supported a 4* individual-domain structure (bulbar, gross motor, fine motor, and respiratory domains). IRT analysis within each domain revealed misfitting items and overlapping item response category thresholds at all time-points, particularly in the gross motor and respiratory domain items. Results indicate that many of the items of the ALSFRS-R may sub-optimally distinguish among varying levels of disability assessed by each domain, particularly in patients with less severe disability. Measure performance improved across time as patient disability severity increased. In conclusion, modifications to select ALSFRS-R items may improve the instrument's specificity to disability level and sensitivity to treatment effects.

  5. G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis: a pilot trial.

    Directory of Open Access Journals (Sweden)

    Thomas Duning

    2011-03-01

    Full Text Available The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF has neuroprotective and -regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS. The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 µg/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS, a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days. The total number of adverse events (AE and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI, brain volumetry, and voxel-based morphometry.Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect

  6. 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.)

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

    International Nuclear Information System (INIS)

    Marini, Cecilia; Cistaro, Angelina; Fania, Piercarlo; Campi, Cristina; Perasso, Annalisa; Massone, Anna Maria; Calvo, Andrea; Moglia, Cristina; Canosa, Antonio; Cammarosano, Stefania; Chio, Adriano; Caponnetto, Claudia; Nobili, Flavio Mariano; Novi, Giovanni; Scialo, Carlo; Mancardi, Gianluigi; Beltrametti, Mauro C.; Buschiazzo, Ambra; Pomposelli, Elena; Morbelli, Silvia; Sambuceti, Gianmario; Bagnara, Maria Claudia; Bruzzi, Paolo; Piana, Michele

    2016-01-01

    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 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, 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 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. 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.)

  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. Implementation of a population-based epidemiological rare disease registry: study protocol of the amyotrophic lateral sclerosis (ALS)--registry Swabia.

    Science.gov (United States)

    Nagel, Gabriele; Unal, Hatice; Rosenbohm, Angela; Ludolph, Albert C; Rothenbacher, Dietrich

    2013-02-17

    The social and medical impact of rare diseases is increasingly recognized. Amyotrophic lateral sclerosis (ALS) is t