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Sample records for lateral sclerosis sera

  1. Effects of amyotrophic lateral sclerosis sera on cultured cholinergic neurons

    International Nuclear Information System (INIS)

    Touzeau, G.; Kato, A.C.

    1983-01-01

    Dissociated monolayer cultures of chick ciliary ganglion neurons have been used to study the effects of control and ALS sera. The cultured neurons survive and extend neurites for a minimum of 2 weeks in a standard tissue culture medium that contains 10% heat-inactivated human serum. Three parameters of the neurons have been examined when cultured in control and ALS sera for 8 to 12 days: (1) neuronal survival, (2) activity of the enzyme choline acetyltransferase, and (3) synthesis of 3 H-acetylcholine using 3 H-choline as precursor. ALS sera cause a small decrease in these three parameters, but this difference is not significant

  2. Amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Leigh P Nigel

    2009-02-01

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

  3. 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.

  4. Clinical neurogenetics: amyotrophic lateral sclerosis.

    Science.gov (United States)

    Harms, Matthew B; Baloh, Robert H

    2013-11-01

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

  5. 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

  6. 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.

  7. Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier.

    Science.gov (United States)

    Shimizu, Fumitaka; Tasaki, Ayako; Sano, Yasuteru; Ju, Mihua; Nishihara, Hideaki; Oishi, Mariko; Koga, Michiaki; Kawai, Motoharu; Kanda, Takashi

    2014-01-01

    Pathological destruction of blood-brain barrier (BBB) has been thought to be the initial key event in the process of developing multiple sclerosis (MS). The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from relapse-remitting MS (RRMS) and secondary progressive MS (SPMS) patients. We evaluated the effects of sera from the patients in the relapse phase of RRMS (RRMS-R), stable phase of RRMS (RRMS-S) and SPMS on the expression of tight junction proteins and vascular cell adhesion protein-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human brain microvascular endothelial cells (BMECs). Sera from the RRMS-R or SPMS patients decreased the claudin-5 protein expression and the TEER in BMECs. In RRMS-R, this effect was restored after adding an MMP inhibitor, and the MMP-2/9 secretion by BMECs was significantly increased after the application of patients' sera. In SPMS, the immunoglobulin G (IgG) purified from patients' sera also decreased the claudin-5 protein expression and the TEER in BMECs. The sera and purified IgG from all MS patients increased the VCAM-1 protein expression in BMECs. The up-regulation of autocrine MMP-2/9 by BMECs after exposure to sera from RRMS-R patients or the autoantibodies against BMECs from SPMS patients can compromise the BBB. Both RRMS-S and SPMS sera increased the VCAM-1 expression in the BBB, thus indicating that targeting the VCAM-1 in the BBB could represent a possible therapeutic strategy for even the stable phase of MS and SPMS.

  8. Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier.

    Directory of Open Access Journals (Sweden)

    Fumitaka Shimizu

    Full Text Available BACKGROUND: Pathological destruction of blood-brain barrier (BBB has been thought to be the initial key event in the process of developing multiple sclerosis (MS. The purpose of the present study was to clarify the possible molecular mechanisms responsible for the malfunction of BBB by sera from relapse-remitting MS (RRMS and secondary progressive MS (SPMS patients. METHODS: We evaluated the effects of sera from the patients in the relapse phase of RRMS (RRMS-R, stable phase of RRMS (RRMS-S and SPMS on the expression of tight junction proteins and vascular cell adhesion protein-1 (VCAM-1, and on the transendothelial electrical resistance (TEER in human brain microvascular endothelial cells (BMECs. RESULTS: Sera from the RRMS-R or SPMS patients decreased the claudin-5 protein expression and the TEER in BMECs. In RRMS-R, this effect was restored after adding an MMP inhibitor, and the MMP-2/9 secretion by BMECs was significantly increased after the application of patients' sera. In SPMS, the immunoglobulin G (IgG purified from patients' sera also decreased the claudin-5 protein expression and the TEER in BMECs. The sera and purified IgG from all MS patients increased the VCAM-1 protein expression in BMECs. CONCLUSIONS: The up-regulation of autocrine MMP-2/9 by BMECs after exposure to sera from RRMS-R patients or the autoantibodies against BMECs from SPMS patients can compromise the BBB. Both RRMS-S and SPMS sera increased the VCAM-1 expression in the BBB, thus indicating that targeting the VCAM-1 in the BBB could represent a possible therapeutic strategy for even the stable phase of MS and SPMS.

  9. 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

  10. Quantitative muscle ultrasonography in amyotrophic lateral sclerosis.

    NARCIS (Netherlands)

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

    2008-01-01

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

  11. 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.

  12. Sleep and Fasciculations in Amyothropic Lateral Sclerosis

    Czech Academy of Sciences Publication Activity Database

    Šonka, K.; Fiksa, J.; Horváth, E.; Kemlink, D.; Süssová, J.; Böhm, J.; Šebesta, Václav; Volná, J.; Nevšímalová, S.

    2004-01-01

    Roč. 8, č. 1 (2004), s. 25-30 ISSN 1432-9123 R&D Projects: GA MZd NF5999 Keywords : amyothropic lateral sclerosis ALS * fasciculation * fragmentary myoclonus * periodic leg movements in sleep PLMS * polysomnography PSG * electromyography EMG * REM sleep Subject RIV: BD - Theory of Information

  13. 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.

  14. Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Hideaki Nishihara

    Full Text Available OBJECTIVE: Effect of fingolimod in multiple sclerosis (MS is thought to involve the prevention of lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system across blood-brain barrier (BBB. However, brain microvascular endothelial cells (BMECs represent a possible additional target for fingolimod in MS patients by directly repairing the function of BBB, as S1P receptors are also expressed by BMECs. In this study, we evaluated the effects of fingolimod on BMECs and clarified whether fingolimod-phosphate restores the BBB function after exposure to MS sera. METHODS: Changes in tight junction proteins, adhesion molecules and transendothelial electrical resistance (TEER in BMECs were evaluated following incubation in conditioned medium with or without fingolimod/fingolimod-phosphate. In addition, the effects of sera derived from MS patients, including those in the relapse phase of relapse-remitting (RR MS, stable phase of RRMS and secondary progressive MS (SPMS, on the function of BBB in the presence of fingolimod-phosphate were assessed. RESULTS: Incubation with fingolimod-phosphate increased the claudin-5 protein levels and TEER values in BMECs, although it did not change the amount of occludin, ICAM-1 or MelCAM proteins. Pretreatment with fingolimod-phosphate restored the changes in the claudin-5 and VCAM-1 protein/mRNA levels and TEER values in BMECs after exposure to MS sera. CONCLUSIONS: Pretreatment with fingolimod-phosphate prevents BBB disruption caused by both RRMS and SPMS sera via the upregulation of claudin-5 and downregulation of VCAM-1 in BMECs, suggesting that fingolimod-phosphate is capable of directly modifying the BBB. BMECs represent a possible therapeutic target for fingolimod in MS patients.

  15. Primary lateral sclerosis mimicking atypical parkinsonism

    DEFF Research Database (Denmark)

    Norlinah, Ibrahim M; Bhatia, Kailash P; Østergaard, Karen

    2007-01-01

    of the atypical parkinsonian syndromes. Here we describe five patients initially referred with a diagnosis of levodopa-unresponsive atypical parkinsonism (n = 4) or primary progressive multiple sclerosis (n = 1), but subsequently found to have features consistent with PLS instead. Onset age varied from 49 to 67......Primary lateral sclerosis (PLS), the upper motor neurone variant of motor neurone disease, is characterized by progressive spinal or bulbar spasticity with minimal motor weakness. Rarely, PLS may present with clinical features resembling parkinsonism resulting in occasional misdiagnosis as one...... in all patients. Anterior horn cell involvement developed in three cases. Early gait disturbances resulting in falls were seen in all patients and none of them responded to dopaminergic medications. Two patients underwent dopamine transporter (DaT) SPECT scanning with normal results. Other features...

  16. 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.

  17. 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).

  18. [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.

  19. 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

  20. Amyotrophic lateral sclerosis associated with pregnancy.

    LENUS (Irish Health Repository)

    Tyagi, A

    2012-02-03

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

  1. 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...

  2. 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

  3. 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

  4. 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

  5. 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

  6. [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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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...

  17. 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.

  18. 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

  19. 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 ...

  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. 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.

  2. 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.

  3. [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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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

  11. 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...

  12. 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…

  13. 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

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

    NARCIS (Netherlands)

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

    2005-01-01

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

  15. 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

  16. 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

  17. 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...

  18. 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...

  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. [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.

  1. 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 ...

  2. 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.)

  3. 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...

  4. 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...

  5. 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...

  6. 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...

  7. 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...

  8. 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 ...

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. Case-control study of amyotrophic lateral sclerosis

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Giovanni Nardo

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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  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. 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

  7. 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.

  8. 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.

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

    Science.gov (United States)

    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.

  10. 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)

  11. 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.

  12. Serum Nogo-A levels are not elevated in amyotrophic lateral sclerosis patients.

    Science.gov (United States)

    Harel, Noam Y; Cudkowicz, Merit E; Brown, Robert H; Strittmatter, Stephen M

    2009-09-01

    Improved biomarkers would facilitate the diagnosis and treatment of amyotrophic lateral sclerosis (ALS). Muscle content of the neuritic outgrowth inhibitor Nogo-A is increased in patients with ALS and other denervating conditions. Seeking a less invasive diagnostic method, we sought to determine whether or not Nogo increases in the serum of ALS patients. We developed a dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) protocol to screen serum samples from 172 ALS patients and 172 healthy controls for Nogo-A immunoreactivity. Unexpectedly, there was a trend toward decreased levels of serum Nogo-A in ALS. Mean serum Nogo-A level in ALS patients was 0.71 nM (95% confidence interval (CI) 0.42-1.00), as opposed to 1.15 nM (95% CI 0.72-1.59) in healthy controls. A significantly larger percentage of healthy control sera (11.0% vs 4.7%) displayed markedly elevated levels of Nogo-A. Additional study is required to determine the factors that lead to elevated Nogo-A levels in a subset of both ALS patients and healthy controls.

  13. 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)

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. Imaging of glia activation in people with primary lateral sclerosis.

    Science.gov (United States)

    Paganoni, Sabrina; Alshikho, Mohamad J; Zürcher, Nicole R; Cernasov, Paul; Babu, Suma; Loggia, Marco L; Chan, James; Chonde, Daniel B; Garcia, David Izquierdo; Catana, Ciprian; Mainero, Caterina; Rosen, Bruce R; Cudkowicz, Merit E; Hooker, Jacob M; Atassi, Nazem

    2018-01-01

    Glia activation is thought to contribute to neuronal damage in several neurodegenerative diseases based on preclinical and human post - mortem studies, but its role in primary lateral sclerosis (PLS) is unknown. To localize and measure glia activation in people with PLS compared to healthy controls (HC). Ten participants with PLS and ten age-matched HCs underwent simultaneous magnetic resonance (MR) and proton emission tomography (PET). The radiotracer [ 11 C]-PBR28 was used to obtain PET-based measures of 18 kDa translocator protein (TSPO) expression, a marker of activated glial cells. MR techniques included a structural sequence to measure cortical thickness and diffusion tensor imaging (DTI) to assess white matter integrity. PET data showed increased [ 11 C]-PBR28 uptake in anatomically-relevant motor regions which co-localized with areas of regional gray matter atrophy and decreased subcortical fractional anisotropy. This study supports a link between glia activation and neuronal degeneration in PLS, and suggests that these disease mechanisms can be measured in vivo in PLS. Future studies are needed to determine the longitudinal changes of these imaging measures and to clarify if MR-PET with [ 11 C]-PBR28 can be used as a biomarker for drug development in the context of clinical trials for PLS.

  2. [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.

  3. [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.

  4. 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.

  5. 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.

  6. 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.

  7. [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.

  8. 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.

  9. 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.

  10. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  12. 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)

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. [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.

  2. 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.

  3. 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.

  4. Cerebro-cerebellar connectivity is increased in primary lateral sclerosis.

    Science.gov (United States)

    Meoded, Avner; Morrissette, Arthur E; Katipally, Rohan; Schanz, Olivia; Gotts, Stephen J; Floeter, Mary Kay

    2015-01-01

    Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS), a long-lived motor neuron disease. Connectivity matrices were constructed from resting state fMRI in 16 PLS patients to identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used to examine structural connections between regions of differing connectivity. PLS patients had 12 regions with increased functional connectivity compared to controls, with a predominance of cerebro-cerebellar connections. Increased functional connectivity was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber tracking detected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  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. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.)

  1. 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.

  2. 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

  3. 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

  4. 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),

  5. 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),

  6. 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

  7. 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.

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  11. 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.

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

    Science.gov (United States)

    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.

  13. 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.

  14. 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.

  15. 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.

  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. 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.

  18. 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.

  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. 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.)

  1. 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

  2. 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.

  3. 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.

  4. 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.)

  5. 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.

  6. Place of death in patients with amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    J. Escarrabill

    2014-07-01

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

  7. 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.

  8. 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

  9. 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)

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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....

  15. Symptomatic treatments for amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Ng, Louisa; Khan, Fary; Young, Carolyn A; Galea, Mary

    2017-01-10

    Motor neuron disease (MND), which is also known as amyotrophic lateral sclerosis (ALS), causes a wide range of symptoms but the evidence base for the effectiveness of the symptomatic treatment therapies is limited. To summarise the evidence from Cochrane Systematic Reviews of all symptomatic treatments for MND. We searched the Cochrane Database of Systematic Reviews (CDSR) on 15 November 2016 for systematic reviews of symptomatic treatments for MND. We assessed the methodological quality of the included reviews using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the GRADE approach. We followed standard Cochrane study (review) selection and data extraction procedures. We reported findings narratively and in tables. We included nine Cochrane Systematic Reviews of interventions to treat symptoms in people with MND. Three were empty reviews with no included randomised controlled trials (RCTs); however, all three reported on non-RCT evidence and the remaining six included mostly one or two studies. We deemed all of the included reviews of high methodological quality. Drug therapy for painThere is no RCT evidence in a Cochrane Systematic Review exploring the efficacy of drug therapy for pain in MND. Treatment for crampsThere is evidence (13 RCTs, N = 4012) that for the treatment of cramps in MND, compared to placebo:- memantine and tetrahydrocannabinol (THC) are probably ineffective (moderate-quality evidence);- vitamin E may have little or no effect (low-quality evidence); and- the effects of L-threonine, gabapentin, xaliproden, riluzole, and baclofen are uncertain as the evidence is either very low quality or the trial specified the outcome but did not report numerical data.The review reported adverse effects of riluzole, but it is not clear whether other interventions had adverse effects. Treatment for spasticityIt is uncertain whether an endurance-based exercise programme improved spasticity or quality of life, measured at three months after the

  16. 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

  17. 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

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

    NARCIS (Netherlands)

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

    2002-01-01

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

  19. 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

  20. 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...

  1. 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

  2. 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

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

    NARCIS (Netherlands)

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

    2015-01-01

    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

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

    Directory of Open Access Journals (Sweden)

    T.L.N. Swamy

    2011-01-01

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

  6. 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;

  7. 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…

  8. 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.

  9. 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

  10. Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population.

    Science.gov (United States)

    Fournier, Christina N; Murphy, Alyssa; Loci, Lorena; Mitsumoto, Hiroshi; Lomen-Hoerth, Catherine; Kisanuki, Yasushi; Simmons, Zachary; Maragakis, Nicholas J; McVey, April L; Al-Lahham, Tawfiq; Heiman-Patterson, Terry D; Andrews, Jinsy; McDonnell, Erin; Cudkowicz, Merit; Atassi, Nazem

    2016-03-01

    The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

  11. 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

  12. 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

  13. 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...

  14. 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.

  15. 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.)

  16. 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…

  17. 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…

  18. 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.

  19. 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.)

  20. 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

  1. 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

  2. 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

  3. 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...

  4. 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.

  5. 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.

  6. 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)…

  7. 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).

  8. [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.

  9. 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...

  10. 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

  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

    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

  12. 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

  13. 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…

  14. 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

  15. 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

  16. 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

  17. 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

  18. [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.

  19. 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.

  20. 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.

  1. 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.

  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. 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.)

  4. 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.

  5. 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

  6. 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...

  7. 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...

  8. 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...

  9. 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 ...

  10. 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...

  11. 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...

  12. 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.

  13. 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

  14. 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.

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    Elif Bakı

    2012-12-01

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

  17. 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.)

  18. 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.

  19. 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...

  20. "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

  1. Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study.

    Science.gov (United States)

    Van Laere, Koen; Vanhee, Annelies; Verschueren, Jolien; De Coster, Liesbeth; Driesen, An; Dupont, Patrick; Robberecht, Wim; Van Damme, Philip

    2014-05-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting the motor system, with extramotor involvement to a variable extent. Biomarkers for early differential diagnosis and prognosis are needed. An autosomal dominant hexanucleotide (GGGGCC) expansion in the noncoding region of the chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent genetic cause of ALS, but its metabolic pattern has not been studied systematically. To evaluate the use of 18fluorodeoxyglucose-positron-emission tomography as a marker of ALS pathology and investigate whether a specific metabolic signature is present in patients with C9orf72 mutations. In total, 81 patients with a suspected diagnosis of ALS at University Hospital Leuven were prospectively investigated. All underwent detailed neurological examination and electrodiagnostic and genetic testing for the major known genetic causes of ALS (C9orf72, SOD1, TARDBP, and FUS). A diagnosis of ALS was made in 70 of 81 patients. Of these, 11 were C9orf72 positive and 59 were C9orf72 negative. In 7 patients, the diagnosis of primary lateral sclerosis was made; 4 patients had progressive muscular atrophy. A screened healthy control population was used for comparison. Positron-emission tomographic data were spatially normalized and analyzed using a predefined volume of interest and a voxel-based analysis (SPM8). Discriminant analysis was done both volume of interest based and voxel based using a support vector machine approach. Compared with control participants, 18fluorodeoxyglucose-positron-emission tomography showed perirolandic and variable prefrontal hypometabolism in most patients. Patients with primary lateral sclerosis showed a similar pattern. Patients with C9orf72-positive ALS had discrete relative hypometabolism in the thalamus and posterior cingulate compared with those with C9orf72-negative ALS. A posteriori-corrected discriminant analysis was able to correctly classify 95% of ALS cases and

  2. 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.

  3. 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.

  4. 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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-10-15

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

  6. Prognostic Factors in Amyotrophic Lateral Sclerosis: A Population-Based Study.

    Science.gov (United States)

    Moura, Mirian Conceicao; Novaes, Maria Rita Carvalho Garbi; Eduardo, Emanoel Junio; Zago, Yuri S S P; Freitas, Ricardo Del Negro Barroso; Casulari, Luiz Augusto

    2015-01-01

    To determine the prognostic factors associated with survival in amyotrophic lateral sclerosis at diagnosis. This retrospective population-based study evaluated 218 patients treated with riluzole between 2005 and 2014 and described their clinical and demographic profiles after the analysis of clinical data and records from the mortality information system in the Federal District, Brazil. Cox multivariate regression analysis was conducted for the parameters found. The study sample consisted of 132 men and 86 women with a mean age at disease onset of 57.2±12.3 years; 77.6% of them were Caucasian. The mean periods between disease onset and diagnosis were 22.7 months among men and 23.5 months among women, and the mean survival periods were 45.7±47.0 months among men and 39.3±29.8 months among women. In addition, 80.3% patients presented non-bulbar-onset amyotrophic lateral sclerosis, and 19.7% presented bulbar-onset. Cox regression analysis indicated worse prognosis for body mass index (BMI) 75 years (RR: 12.47, 95% CI: 3.51-44.26), and bulbar-onset (RR: 4.56, 95% CI: 2.06-10.12). Electromyography did not confirm the diagnosis in 55.6% of the suspected cases and in 27.9% of the bulbar-onset cases. The factors associated with lower survival in amyotrophic lateral sclerosis were age >75 years, BMI <25 kg/m2, and bulbar-onset.

  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. 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.

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

    Science.gov (United States)

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

    2015-11-01

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

  10. [Regularities of fixation of brain serum antibodies from patients with lateral amyotrophic sclerosis in rabbit CNS].

    Science.gov (United States)

    Musaeva, L S; Gannyshkina, I V; Zavalishin, I A; Markova, E D; Ivanova-Smolenskaia, I A

    2002-01-01

    Kuhns' indirect immunofluorescent test was used to study fixation of serum brain antibodies (Ab) of patients with bulbar, cervicothoracic, lumbosacral lateral amyotropic sclerosis (LAS) on brain sections of rabbits. The disease is characterized by formation of brain Ab complementary to various structures of nervous and glial cells, myelin of fibers from different conducting systems, vessels which exhibit both common and individual antigenic properties. It was found that fixation of antineuronal, antimyelin brain Ab of patients with bulbar, cervicothoracic and lumbosacral LAS in different CNS structures varies.

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

    Directory of Open Access Journals (Sweden)

    Karen Fontes Luchesi

    2014-03-01

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

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

    International Nuclear Information System (INIS)

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

    1982-01-01

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

  13. Efficacy of peptide nucleic acid and selected conjugates against specific cellular pathologies of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Browne, Elisse C; Parakh, Sonam; Duncan, Luke F; Langford, Steven J; Atkin, Julie D; Abbott, Belinda M

    2016-04-01

    Cellular studies have been undertaken on a nonamer peptide nucleic acid (PNA) sequence, which binds to mRNA encoding superoxide dismutase 1, and a series of peptide nucleic acids conjugated to synthetic lipophilic vitamin analogs including a recently prepared menadione (vitamin K) analog. Reduction of both mutant superoxide dismutase 1 inclusion formation and endoplasmic reticulum stress, two of the key cellular pathological hallmarks in amyotrophic lateral sclerosis, by two of the prepared PNA oligomers is reported for the first time. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  14. Evidence for a dopaminergic deficit in sporadic amyotrophic lateral sclerosis on positron emission scanning

    International Nuclear Information System (INIS)

    Takahashi, Hirohide; Snow, B.J.; Bhatt, M.H.; Peppard, R.; Eisen, A.; Calne, D.B.

    1993-01-01

    Although rare, the chronic neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and idiopathic parkinsonism coexist to a greater degree than expected by chance. This suggests that patients with ALS may have subclinical lesions of the nigrostriatal dopaminergic pathway. To study this hypothesis, the authors did positron emission tomography with 6-fluorodopa on 16 patients with sporadic ALS and without extrapyramidal disease, and compared the results with age-matched controls. They found a significant progressive fall in 6-fluorodopa uptake with time since diagnosis, and reduced dopaminergic function in 3 patients with ALS of long duration. This supports the hypothesis that ALS and IP may share pathogenesis, and, perhaps, etiology

  15. Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges

    Science.gov (United States)

    Marangi, Giuseppe; Traynor, Bryan J.

    2018-01-01

    The genetic architecture of amyotrophic lateral sclerosis (ALS) is being increasingly understood. In this far-reaching review, we examine what is currently known about ALS genetics and how these genes were initially identified. We also discuss the various types of mutations that might underlie this fatal neurodegenerative condition and outline some of the strategies that might be useful in untangling them. These include expansions of short repeat sequences, common and low-frequency genetic variations, de novo mutations, epigenetic changes, somatic mutations, epistasis, oligogenic and polygenic hypotheses. PMID:25316630

  16. Brugada syndrome in a patient with amyotrophic lateral sclerosis: a case report.

    Science.gov (United States)

    Battineni, Anusha; Gummi, Rohit; Mullaguri, Naresh; Govindarajan, Raghav

    2017-07-14

    Amyotrophic lateral sclerosis is a fatal neuromuscular disorder characterized by progressive death of the upper and lower motor neurons in the central nervous system. Patients with this disease die mostly as a result of respiratory failure; however, owing to prolonged survival through assisted ventilation, cardiovascular causes are increasingly responsible for mortality. We report what is to the best of our knowledge the first case of type 2 Brugada syndrome causing ventricular tachyarrhythmia and cardiac arrest in a patient with upper limb onset amyotrophic lateral sclerosis. A 48-year-old Caucasian woman with a significant past medical history of papillary thyroid carcinoma status postresection, pulmonary embolism on anticoagulation, and a recent diagnosis of right upper limb-onset amyotrophic lateral sclerosis presented to the emergency department of our hospital with acute on chronic shortness of breath. On further evaluation, she was found to have hypoxic and hypercapnic respiratory failure and was placed on bilevel positive airway pressure ventilation. Her 12-lead electrocardiogram showed sinus rhythm with J-point elevation, saddle-shaped ST segment elevation, predominantly in V1 and V2 with no significant QTc prolongation. No troponin elevation was noted in her laboratory workup. Because she was unable to protect her airway, a decision was made to intubate her. After 1 minute of induction with etomidate and succinylcholine, she went into pulseless ventricular tachycardia and fibrillation requiring three cycles of cardiopulmonary resuscitation with high-quality chest compressions, three doses of epinephrine, and a loading dose of amiodarone prior to return of spontaneous circulation. She was further evaluated by cardiology services and was diagnosed with type 2 Brugada syndrome, for which she was started on quinidine. Her respiratory failure and the drugs she received for intubation likely caused her ventricular tachycardia to occur in conjunction with an

  17. [Types of ventilatory support and their indications in amyotrophic lateral sclerosis].

    Science.gov (United States)

    Perrin, C

    2006-06-01

    Respiratory muscle weakness represents the major cause of mortality in patients with amyotrophic lateral sclerosis (ALS). As a result, ventilatory assistance is an important part of disease management. Nowadays, noninvasive ventilation (NIV) has become the first choice modality for most patients and represents an alternative to tracheostomy intermittent positive-pressure ventilation. Although, some consensus guidelines have been proposed to initiate NIV in patients with restrictive chronic respiratory failure, these criteria are discussed regarding ALS. While the current consensus recommends that NIV may be used in symptomatic patients with hypercapnia or forced vital capacityNIV is proposed in the literature and reported in this paper.

  18. Amyotrophic lateral sclerosis and organ donation: is there risk of disease transmission?

    Science.gov (United States)

    Holmes, Brandon B; Diamond, Marc I

    2012-12-01

    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 close longitudinal follow-up of recipients when harvesting organs from individuals with neurodegenerative disease, especially dominantly inherited forms. Copyright © 2012 American Neurological Association.

  19. Tracheomegaly Secondary to Tracheotomy Tube Cuff in Amyotrophic Lateral Sclerosis: A Case Report.

    Science.gov (United States)

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

    2015-10-01

    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 ALS develops repeat air leakage around the tracheotomy tube or rupture of tracheotomy tube cuff.

  20. [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.

  1. 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

  2. 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.

  3. 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.

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

    Science.gov (United States)

    Ram, Shri

    2016-10-01

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

  5. Tracheostomy and invasive mechanical ventilation in amyotrophic lateral sclerosis: decision-making factors and survival analysis.

    Science.gov (United States)

    Kimura, Fumiharu

    2016-04-28

    Invasive and/or non-invasive mechanical ventilation are most important options of respiratory management in amyotrophic lateral sclerosis. We evaluated the frequency, clinical characteristics, decision-making factors about ventilation and survival analysis of 190 people with amyotrophic lateral sclerosis patients from 1990 until 2013. Thirty-one percentage of patients underwent tracheostomy invasive ventilation with the rate increasing more than the past 20 years. The ratio of tracheostomy invasive ventilation in patients >65 years old was significantly increased after 2000 (25%) as compared to before (10%). After 2010, the standard use of non-invasive ventilation showed a tendency to reduce the frequency of tracheostomy invasive ventilation. Mechanical ventilation prolonged median survival (75 months in tracheostomy invasive ventilation, 43 months in non-invasive ventilation vs natural course, 32 months). The life-extending effects by tracheostomy invasive ventilation were longer in younger patients ≤65 years old at the time of ventilation support than in older patients. Presence of partners and care at home were associated with better survival. Following factors related to the decision to perform tracheostomy invasive ventilation: patients ≤65 years old: greater use of non-invasive ventilation: presence of a spouse: faster tracheostomy: higher progression rate; and preserved motor functions. No patients who underwent tracheostomy invasive ventilation died from a decision to withdraw mechanical ventilation. The present study provides factors related to decision-making process and survival after tracheostomy and help clinicians and family members to expand the knowledge about ventilation.

  6. 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.

  7. Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology and survival.

    Science.gov (United States)

    Beard, John D; Kamel, Freya

    2015-01-01

    Rates of amyotrophic lateral sclerosis (ALS) have been reported to be higher among US military veterans, who currently number more than 21 million, but the causal factor(s) has not been identified. We conducted a review to examine the weight of evidence for associations between military service, deployments, and exposures and ALS etiology and survival. Thirty articles or abstracts published through 2013 were reviewed. Although the current evidence suggests a positive association with ALS etiology, it is too limited to draw firm conclusions regarding associations between military service and ALS etiology or survival. Some evidence suggests that deployment to the 1990-1991 Persian Gulf War may be associated with ALS etiology, but there is currently no strong evidence that any particular military exposure is associated with ALS etiology. Future studies should address the limitations of previous ones, such as reliance on mortality as a surrogate for incidence, a dearth of survival analyses, lack of clinical data, low statistical power, and limited exposure assessment. The Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis (GENEVA) Study is one such study, but additional research is needed to determine whether military-related factors are associated with ALS and to assess potential prevention strategies. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  8. Metabolomics in amyotrophic lateral sclerosis: how far can it take us?

    Science.gov (United States)

    Blasco, H; Patin, F; Madji Hounoum, B; Gordon, P H; Vourc'h, P; Andres, C R; Corcia, P

    2016-03-01

    Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. Alongside identification of aetiologies, development of biomarkers is a foremost research priority. Metabolomics is one promising approach that is being utilized in the search for diagnosis and prognosis markers. Our aim is to provide an overview of the principal research in metabolomics applied to ALS. References were identified using PubMed with the terms 'metabolomics' or 'metabolomic' and 'ALS' or 'amyotrophic lateral sclerosis' or 'MND' or 'motor neuron disorders'. To date, nine articles have reported metabolomics research in patients and a few additional studies examined disease physiology and drug effects in patients or models. Metabolomics contribute to a better understanding of ALS pathophysiology but, to date, no biomarker has been validated for diagnosis, principally due to the heterogeneity of the disease and the absence of applied standardized methodology for biomarker discovery. A consensus on best metabolomics methodology as well as systematic independent validation will be an important accomplishment on the path to identifying the long-awaited biomarkers for ALS and to improve clinical trial designs. © 2016 EAN.

  9. Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Masamitsu Okada

    2018-06-01

    Full Text Available Background and purpose: Oxidative stress has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS. Edaravone, a free radical scavenger, was approved as a therapeutic drug for ALS in 2015 in Japan. A phase 3 clinical trial demonstrated a smaller decline in ALS functional scale scores compared with placebo. However, the long-term effects of edaravone on ALS patients remain unclear. This study aimed to retrospectively investigate the long-term effects of edaravone on the survival of ALS patients. Methods: We retrospectively analyzed 27 consecutive patients with ALS who were treated with edaravone and 30 consecutive ALS patients who were not treated with edaravone between 2010 and 2016. Results: The differences of ALSFRS-R scores from baseline to 6 months was significantly reduced in the edaravone group, compared to the control group. The changes in serum creatinine, as a possible marker of ALS severity, from baseline to 6 and 12 months were significantly improved in the edaravone group, compared to the control group. The survival rate was significantly improved in the edaravone group compared with control patients. Conclusion: Our retrospective single-center analysis suggests slower progression and better prognosis of ALS patients with edaravone treatment. Further investigation, including prospective multicenter analysis, is warranted to confirm the usefulness of edaravone for a better prognosis of ALS. Keywords: Amyotrophic lateral sclerosis, Oxidative stress, Edaravone, Long-term effect, Survival

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

    International Nuclear Information System (INIS)

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

    2014-01-01

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

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

    Science.gov (United States)

    Hanrieder, Jörg; Ewing, Andrew G.

    2014-06-01

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

  12. Daytime Mouthpiece for Continuous Noninvasive Ventilation in Individuals With Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Bédard, Marie-Eve; McKim, Douglas A

    2016-10-01

    Noninvasive ventilation (NIV) is commonly used to provide ventilatory support for individuals with amyotrophic lateral sclerosis (ALS). Once 24-h ventilation is required, the decision between invasive tracheostomy ventilation and palliation is often faced. This study describes the use and outcomes of daytime mouthpiece ventilation added to nighttime mask ventilation for continuous NIV in subjects with ALS as an effective alternative. This was a retrospective study of 39 subjects with ALS using daytime mouthpiece ventilation over a 17-y period. Thirty-one subjects were successful with mouthpiece ventilation, 2 were excluded, 2 stopped because of lack of motivation, and 4 with bulbar subscores of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (b-ALSFRS-R) between 0 and 3 physically failed to use it consistently. No subject in the successful group had a b-ALSFRS-R score of NIV and mouthpiece ventilation were 648 (176-2,188) and 286 (41-1,769) d, respectively. Peak cough flow with lung-volume recruitment >180 L/min at initiation of mouthpiece ventilation was associated with a longer survival (637 ± 468 vs 240 ± 158 d (P = .01). Mouthpiece ventilation provides effective ventilation and prolonged survival for individuals with ALS requiring full-time ventilatory support and maintaining adequate bulbar function. Copyright © 2016 by Daedalus Enterprises.

  13. Absence of airway secretion accumulation predicts tolerance of noninvasive ventilation in subjects with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Vandenberghe, Nadia; Vallet, Anne-Evelyne; Petitjean, Thierry; Le Cam, Pierre; Peysson, Stéphane; Guérin, Claude; Dailler, Frédéric; Jay, Sylvie; Cadiergue, Vincent; Bouhour, Françoise; Court-Fortune, Isabelle; Camdessanche, Jean-Philippe; Antoine, Jean-Christophe; Philit, François; Beuret, Pascal; Bin-Dorel, Sylvie; Vial, Christophe; Broussolle, Emmanuel

    2013-09-01

    To assess factors that predict good tolerance of noninvasive ventilation (NIV), in order to improve survival and quality of life in subjects with amyotrophic lateral sclerosis. We conducted a prospective study in subjects with amyotrophic lateral sclerosis and requiring NIV. The primary end point was NIV tolerance at 1 month. Subjects, several of whom failed to complete the study, were classified as "tolerant" or "poorly tolerant," according to the number of hours of NIV use (more or less than 4 h per night, respectively). Eighty-one subjects, 73 of whom also attended the 1-month follow-up visit, participated over 34 months. NIV tolerance after the first day of utilization predicted tolerance at 1 month (77.6% and 75.3% of subjects, respectively). Multivariate analysis disclosed 3 factors predicting good NIV tolerance: absence of airway secretions accumulation prior to NIV onset (odds ratio 11.5); normal bulbar function at initiation of NIV (odds ratio 8.5); and older age (weakly significant, odds ratio 1.1). Our study reveals 3 factors that are predictive of good NIV tolerance, in particular the absence of airway secretion accumulation, which should prompt NIV initiation before its appearance.

  14. 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.

  15. A Case of Morvan Syndrome Mimicking Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.

    Science.gov (United States)

    Freund, Brin; Maddali, Manoj; Lloyd, Thomas E

    2016-06-01

    Morvan syndrome is a rare autoimmune/paraneoplastic disorder involving antibodies to the voltage-gated potassium channel complex. It is defined by subacute encephalopathy, neuromuscular hyperexcitability, dysautonomia, and sleep disturbance. It may present a diagnostic dilemma when trying to differentiate from amyotrophic lateral sclerosis with frontotemporal dementia. A 76-year-old man with a history of untreated prostate adenocarcinoma was evaluated for subacute cognitive decline, diffuse muscle cramps, and hyponatremia. MRI demonstrated atrophy most prominent in the frontal and temporal regions. Electromyography (EMG) demonstrated diffuse myokymia/neuromyotonia. Polysomnography lacked REM and N3 sleep. Paraneoplastic panel detected antibodies to voltage-gated potassium channel complex (CASPR2 subtype). It is difficult to differentiate between Morvan syndrome and amyotrophic lateral sclerosis with frontotemporal dementia with examination and neuroimaging alone. There may be a link between Morvan syndrome and prostate adenocarcinoma which could help with screening/diagnosis. The authors found that laboratory and neurophysiological tests are indispensable in diagnosing and treating Morvan syndrome.

  16. 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.

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

    Directory of Open Access Journals (Sweden)

    A. Yamanami-Irioka

    2011-10-01

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

  18. Transcranial brainstem sonography as a diagnostic tool for amyotrophic lateral sclerosis.

    Science.gov (United States)

    Prell, Tino; Schenk, Annekathrin; Witte, Otto W; Grosskreutz, Julian; Günther, Albrecht

    2014-06-01

    Diagnosing amyotrophic lateral sclerosis (ALS) can be difficult, particularly in the early stage of disease; therefore, we evaluated the use of transcranial stem sonography (TCS) to improve early detection of the disease. In this cross-sectional study, 94 patients with sporadic ALS and 46 age- and gender-matched healthy controls were evaluated by TCS according to a standardized protocol used to diagnose Parkinson's disease. Approximately half (48%) of the patients with ALS showed a clear (> 0.25 cm(2)) mesencephalic hyperechogenic structure, 20% showed a possible (laterally. In conclusion, although the neuropathological correlation to hyperechogenicity remains unclear, TCS is an easy, feasible and reproducible technique that could serve as an additional diagnostic tool and as a surrogate biomarker in ALS.

  19. 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

  20. 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...

  1. Two consecutive pregnancies in early and late stage of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Sarafov, Stayko; Doitchinova, Maryana; Karagiozova, Zhvka; Slancheva, Boriana; Dengler, Reinhard; Petri, Susanne; Kollewe, Katja

    2009-01-01

    There are few reports on pregnancies in sporadic and familial amyotrophic lateral sclerosis (ALS). We report on a young woman with sporadic ALS who gave birth twice during the course of her disease. The first pregnancy occurred 13 months after the onset of symptoms, and one month after diagnosis. The pregnancy was uncomplicated and resulted in vaginal delivery of a healthy boy. Fifteen months later, when she was already bed-ridden, she became pregnant again. She received a percutaneous endoscopic gastrostomy in the 21st gestational week and underwent early Caesarean section in the 34th week of gestation. The child was ventilated for 72 h in a neonatological unit. The patient was tracheotomized and ventilated two months later, i.e. 47 months after symptom onset, and died nine months later from gastrointestinal haemorrhage. Her two children have developed without abnormalities to date. This case confirms that pregnancies in early-stage ALS can develop normally and may result in uncomplicated vaginal delivery. Pregnancies in late stages may be critical for mother and child, and early delivery by Caesarean section may become necessary although neonatal outcome can be good.

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

    Directory of Open Access Journals (Sweden)

    van Eijk RPA

    2018-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Anne Vejux

    2018-01-01

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

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

    Science.gov (United States)

    Vejux, Anne; Namsi, Amira; Nury, Thomas; Moreau, Thibault; Lizard, Gérard

    2018-01-01

    Amyotrophic lateral sclerosis (ALS) is a non-demyelinating neurodegenerative disease in adults with motor disorders. Two forms exist: a sporadic form (90% of cases) and a family form due to mutations in more than 20 genes including the Superoxide dismutase 1, TAR DNA Binding Protein, Fused in Sarcoma, chromosome 9 open reading frame 72 and VAPB genes. The mechanisms associated with this pathology are beginning to be known: oxidative stress, glutamate excitotoxicity, protein aggregation, reticulum endoplasmic stress, neuroinflammation, alteration of RNA metabolism. In various neurodegenerative diseases, such as Alzheimer’s disease or multiple sclerosis, the involvement of lipids is increasingly suggested based on lipid metabolism modifications. With regard to ALS, research has also focused on the possible involvement of lipids. Lipid involvement was suggested for clinical arguments where changes in cholesterol and LDL/HDL levels were reported with, however, differences in positivity between studies. Since lipids are involved in the membrane structure and certain signaling pathways, it may be considered to look for oxysterols, mainly 25-hydroxycholesterol and its metabolites involved in immune response, or phytosterols to find suitable biomarkers for this pathology. PMID:29445325

  5. Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Patten, Shunmoogum A; Aggad, Dina; Martinez, Jose; Tremblay, Elsa; Petrillo, Janet; Armstrong, Gary Ab; La Fontaine, Alexandre; Maios, Claudia; Liao, Meijiang; Ciura, Sorana; Wen, Xiao-Yan; Rafuse, Victor; Ichida, Justin; Zinman, Lorne; Julien, Jean-Pierre; Kabashi, Edor; Robitaille, Richard; Korngut, Lawrence; Parker, J Alexander; Drapeau, Pierre

    2017-11-16

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.

  6. Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise.

    Science.gov (United States)

    Lanfranconi, F; Ferri, A; Corna, G; Bonazzi, R; Lunetta, C; Silani, V; Riva, N; Rigamonti, A; Maggiani, A; Ferrarese, C; Tremolizzo, L

    2017-06-07

    This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O 2 uptake ([Formula: see text]O 2peak ), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]E peak ). pALS displayed: (1) 44% lower [Formula: see text]O 2peak vs. CTRL (p motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O 2 transport and utilization chain.

  7. Cutaneous somatic and autonomic nerve TDP-43 deposition in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Ren, Yuting; Liu, Wenxiu; Li, Yifan; Sun, Bo; Li, Yanran; Yang, Fei; Wang, Hongfen; Li, Mao; Cui, Fang; Huang, Xusheng

    2018-05-26

    To evaluate the involvement of the sensory and autonomic nervous system in amyotrophic lateral sclerosis (ALS) and to determine whether TDP-43/pTDP-43 deposits in skin nerve fibers signify a valuable biomarker for ALS. Eighteen patients with ALS and 18 age- and sex-matched control subjects underwent physical examinations, in addition to donating skin biopsies from the distal leg. The density of epidermal, Meissner's corpuscle (MC), sudomotor, and pilomotor nerve fibers were measured. Confocal microscopy was used to determine the cutaneous somatic and autonomic nerve fiber density and TDP-43/pTDP-43 deposition. Intraepidermal nerve fiber density (IENFD) was reduced in individuals with ALS (P nerve fiber density (SGNFD) (P nerve fiber density (PNFD) (P nerve fibers may indicate an important role in the underlying pathogenesis of ALS. This observation might be used as a potential biomarker for diagnosing ALS.

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

    Science.gov (United States)

    Wang, Lixia; Yi, Fei; Fu, Lina; Yang, Jiping; Wang, Si; Wang, Zhaoxia; Suzuki, Keiichiro; Sun, Liang; Xu, Xiuling; Yu, Yang; Qiao, Jie; Belmonte, Juan Carlos Izpisua; Yang, Ze; Yuan, Yun; Qu, Jing; Liu, Guang-Hui

    2017-05-01

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

  9. Semantic memory assessment in 15 patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Hervieu-Bègue, M; Rouaud, O; Graule Petot, A; Catteau, A; Giroud, M

    2016-01-01

    A total of 30 to 50% of amyotrophic lateral sclerosis patients suffer from cognitive disorders. The aim of the study is to characterize these disorders and to assess semantic memory in non-demented ALS patients. The secondary aim is to look for a link between disease type and neuropsychological characteristics. Patients were followed in an ALS center in Dijon. The following neuropsychological tests were used in this study: Folstein test, BREF test, verbal fluency, Isaac test, GRESEM test and TOP 30 test. Fifteen ALS patients were included. Nine of them (60%) were suffering from a semantic memory disorder. There was no correlation between ALS characteristics and the semantic memory disorder. This is the first study to reveal a semantic memory disorder in ALS. This result accentuates the hypothesis that ALS and semantic dementia are two phenotypes of the same degenerative process linked to TDP 43 proteinopathy. Copyright © 2016. Published by Elsevier Masson SAS.

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

    Directory of Open Access Journals (Sweden)

    Adam K. Walker

    2011-01-01

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

  11. 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.

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

    Directory of Open Access Journals (Sweden)

    Mariela Bettini

    2011-12-01

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

  13. [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.

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

    Directory of Open Access Journals (Sweden)

    Lixia Wang

    2017-04-01

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

  15. Association study between XRCC1 gene polymorphisms and sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Coppedè, Fabio; Migheli, Francesca; Lo Gerfo, Annalisa; Fabbrizi, Maria Rita; Carlesi, Cecilia; Mancuso, Michelangelo; Corti, Stefania; Mezzina, Nicoletta; del Bo, Roberto; Comi, Giacomo P; Siciliano, Gabriele; Migliore, Lucia

    2010-01-01

    The aim of the present study was to investigate the possible contribution of three common functional polymorphisms in the DNA repair protein X-ray repair cross-complementing group 1 (XRCC1), namely Arg194Trp (rs1799782), Arg280His (rs25489) and Arg399Gln (rs25487), to sporadic amyotrophic lateral sclerosis (SALS). We genotyped 206 Italian SALS patients and 203 matched controls for XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms by means of PCR/RFLP technique, searching for association between any of the studied polymorphisms and disease risk, age and site of onset. We observed a statistically significant difference in XRCC1 Gln399 allele frequencies between SALS cases and controls (0.39/0.28; p=0.001). The present study suggests that the XRCC1 Arg399Gln polymorphism might contribute to SALS risk.

  16. Maple Syrup Decreases TDP-43 Proteotoxicity in a Caenorhabditis elegans Model of Amyotrophic Lateral Sclerosis (ALS).

    Science.gov (United States)

    Aaron, Catherine; Beaudry, Gabrielle; Parker, J Alex; Therrien, Martine

    2016-05-04

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing death of the motor neurons. Proteotoxicity caused by TDP-43 protein is an important aspect of ALS pathogenesis, with TDP-43 being the main constituent of the aggregates found in patients. We have previously tested the effect of different sugars on the proteotoxicity caused by the expression of mutant TDP-43 in Caenorhabditis elegans. Here we tested maple syrup, a natural compound containing many active molecules including sugars and phenols, for neuroprotective activity. Maple syrup decreased several age-dependent phenotypes caused by the expression of TDP-43(A315T) in C. elegans motor neurons and requires the FOXO transcription factor DAF-16 to be effective.

  17. Monitoring Progression of Amyotrophic Lateral Sclerosis Using Ultrasound Morpho-Textural Muscle Biomarkers: A Pilot Study.

    Science.gov (United States)

    Martínez-Payá, Jacinto J; Ríos-Díaz, José; Medina-Mirapeix, Francesc; Vázquez-Costa, Juan F; Del Baño-Aledo, María Elena

    2018-01-01

    The need is increasing for progression biomarkers that allow the loss of motor neurons in amyotrophic lateral sclerosis (ALS) to be monitored in clinical trials. In this prospective longitudinal study, muscle thickness, echointensity, echovariation and gray level co-occurrence matrix textural features are examined as possible progression ultrasound biomarkers in ALS patients during a 5-mo follow-up period. We subjected 13 patients to 3 measurements for 20 wk. They showed a significant loss of muscle, an evident tendency to loss of thickness and increased echointensity and echovariation. In regard to textural parameters, muscle heterogeneity tended to increase as a result of the neoformation of non-contractile tissue through denervation. Considering some limitations of the study, the quantitative muscle ultrasound biomarkers evaluated showed a promising ability to monitor patients affected by ALS. Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.

  18. 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.

  19. Cortical T2 signal shortening in amyotrophic lateral sclerosis is not due to iron deposits

    Energy Technology Data Exchange (ETDEWEB)

    Hecht, M.J.; Neundoerfer, B. [University of Erlangen-Nurenberg, Department of Neurology, Erlangen (Germany); Fellner, C.; Fellner, F.A. [University of Erlangen-Nurenberg, Institute of Diagnostic Radiology, Erlangen (Germany); Landes-Nervenklinik Wagner-Jauregg, Institute of Radiology, Linz (Austria); Schmid, A. [University of Erlangen-Nurenberg, Institute of Diagnostic Radiology, Erlangen (Germany)

    2005-11-01

    Signal shortening of the motor cortex in T2-weighted MR images is a frequent finding in patients with amyotrophic lateral sclerosis (ALS). The cause of signal shortening in ALS is unknown, although iron deposits have been suggested. To test this hypothesis, we acquired T2*-weighted gradient-echo (GRE) MR images in addition to T2-weighted turbo spin-echo in 69 patients with ALS. Signal shortening in T2-weighted images was found in 31 patients. In T2*-weighted GRE images, only three patients had signal shortening. One patient with additional bifrontal haemorrhage had frontal but no motor cortex signal shortening. Iron deposits do not cause cortical signal shortening in patients with ALS predominantly. Other factors are presumably more important in the generation of cortical T2 shortening in ALS. (orig.)

  20. Elemental imbalance studies by INAA on extra neural tissues from amyotrophic lateral sclerosis patients

    International Nuclear Information System (INIS)

    Tandon, L.; Ehmann, W.D.

    1995-01-01

    Human kidney and liver tissues were studied for generalized elemental imbalances in amyotrophic lateral sclerosis (ALS) by instrumental neutron activation analysis (INAA). Iron was significantly increased (p<0.05) in ALS kidneys and Co and Fe (marginal, p<0.10) were increased in ALS liver compared with their respective controls. Mercury values were almost two-fold higher for ALS kidney and 17% higher for ALS liver as compared with their respective controls, However, the Hg data exhibited large variations and ALS-control differences were not significant. Data from the present study are discussed with reference to the role of metallothioneins (MT) in ALS, and a possible linkage between a free radical mediated mechanism and degeneration of cells in ALS is also explored. (author). 43 refs., 2 tabs

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

    Science.gov (United States)

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

    2017-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Jia Liu

    2017-08-01

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

  3. 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.)

  4. 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)

  5. Cortical T2 signal shortening in amyotrophic lateral sclerosis is not due to iron deposits

    International Nuclear Information System (INIS)

    Hecht, M.J.; Neundoerfer, B.; Fellner, C.; Fellner, F.A.; Schmid, A.

    2005-01-01

    Signal shortening of the motor cortex in T2-weighted MR images is a frequent finding in patients with amyotrophic lateral sclerosis (ALS). The cause of signal shortening in ALS is unknown, although iron deposits have been suggested. To test this hypothesis, we acquired T2*-weighted gradient-echo (GRE) MR images in addition to T2-weighted turbo spin-echo in 69 patients with ALS. Signal shortening in T2-weighted images was found in 31 patients. In T2*-weighted GRE images, only three patients had signal shortening. One patient with additional bifrontal haemorrhage had frontal but no motor cortex signal shortening. Iron deposits do not cause cortical signal shortening in patients with ALS predominantly. Other factors are presumably more important in the generation of cortical T2 shortening in ALS. (orig.)

  6. 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.

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

    Directory of Open Access Journals (Sweden)

    Mohammad Hasan Namazi

    2014-01-01

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

  8. Functional Connectivity Changes in Resting-State EEG as Potential Biomarker for Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Iyer, Parameswaran Mahadeva; Egan, Catriona; Pinto-Grau, Marta; Burke, Tom; Elamin, Marwa; Nasseroleslami, Bahman; Pender, Niall; Lalor, Edmund C; Hardiman, Orla

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is heterogeneous and overlaps with frontotemporal dementia. Spectral EEG can predict damage in structural and functional networks in frontotemporal dementia but has never been applied to ALS. 18 incident ALS patients with normal cognition and 17 age matched controls underwent 128 channel EEG and neuropsychology assessment. The EEG data was analyzed using FieldTrip software in MATLAB to calculate simple connectivity measures and scalp network measures. sLORETA was used in nodal analysis for source localization and same methods were applied as above to calculate nodal network measures. Graph theory measures were used to assess network integrity. Cross spectral density in alpha band was higher in patients. In ALS patients, increased degree values of the network nodes was noted in the central and frontal regions in the theta band across seven of the different connectivity maps (pEEG has potential utility as a biomarker in ALS.

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

    Science.gov (United States)

    Bede, Peter; Oliver, David; Stodart, James; van den Berg, Leonard; Simmons, Zachary; O Brannagáin, Doiminic; Borasio, Gian Domenico; Hardiman, Orla

    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. To conduct a systematic analysis of the type, level and timing of specialist palliative care intervention in ALS. Despite an international consensus that ALS management should adopt a multidisciplinary approach, integration of palliative care into ALS management varies considerably across health care systems. Late referral to palliative services in ALS is not uncommon and may impact negatively on the quality of life of ALS patients and their caregivers. However, common themes and principles of engagement can be identified across different jurisdictions, and measurement systems have been established that can assess the impact of palliative care intervention. There is considerable evidence that palliative care intervention improves quality of life in patients and carers. International consensus guidelines would assist in the development of a framework for active palliative care engagement in ALS and other neurodegenerative diseases.

  10. A protocol for identification of early bulbar signs in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Ball, L J; Willis, A; Beukelman, D R; Pattee, G L

    2001-10-15

    The purpose of this project is to identify characteristics that may be of assistance in establishing the diagnosis and monitoring early progression of bulbar dysfunction in patients with Amyotrophic Lateral Sclerosis (ALS). Early identification of bulbar dysfunction would assist in clinical trials and management decisions. A database of 218 clinic visits of patients with ALS was developed and formed the basis for these analyses. As a framework for the description of our methodology, the Disablement Model [World Health Organization. WHO International classification of impairment, activity, and participation: beginner's guide. In: WHO, editor. Beta-1 draft for field trials; 1999] was utilized. Our data identified that the strongest early predictors of bulbar speech dysfunction include altered voice quality (laryngeal control), speaking rate, and communication effectiveness. A protocol for measuring these speech parameters was therefore undertaken. This paper presents the protocol used to measure these bulbar parameters.

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

    Science.gov (United States)

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

    2014-04-01

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

  12. [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.

  13. 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.

  14. Pattern Differences of Small Hand Muscle Atrophy in Amyotrophic Lateral Sclerosis and Mimic Disorders.

    Science.gov (United States)

    Fang, Jia; Liu, Ming-Sheng; Guan, Yu-Zhou; Du, Hua; Li, Ben-Hong; Cui, Bo; Ding, Qing-Yun; Cui, Li-Ying

    2016-04-05

    Amyotrophic lateral sclerosis (ALS) and some mimic disorders, such as distal-type cervical spondylotic amyotrophy (CSA), Hirayama disease (HD), and spinobulbar muscular atrophy (SBMA) may present with intrinsic hand muscle atrophy. This study aimed to investigate different patterns of small hand muscle involvement in ALS and some mimic disorders. We compared the abductor digiti minimi/abductor pollicis brevis (ADM/APB) compound muscle action potential (CMAP) ratios between 200 ALS patients, 95 patients with distal-type CSA, 88 HD patients, 43 SBMA patients, and 150 normal controls. The ADM/APB CMAP amplitude ratio was significantly higher in the ALS patients (P mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders, and may aid in distinguishing between ALS and mimic disorders.

  15. 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.

  16. 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.

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

    Science.gov (United States)

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

    2017-08-01

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

  18. 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.

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

    Science.gov (United States)

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

    2017-12-01

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

  20. Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis survival.

    Directory of Open Access Journals (Sweden)

    John D Beard

    Full Text Available Military veterans may have higher rates of amyotrophic lateral sclerosis (ALS mortality than non-veterans. Few studies, with sparse exposure information and mixed results, have studied relationships between military-related factors and ALS survival. We evaluated associations between military-related factors and ALS survival among U.S. military veteran cases.We followed 616 medical record-confirmed cases from enrollment (2005-2010 in the Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis study until death or July 25, 2013, whichever came first. We ascertained vital status information from several sources within the Department of Veterans Affairs. We obtained information regarding military service, deployments, and 39 related exposures via standardized telephone interviews. We used Cox proportional hazards regression models to estimate hazard ratios (HRs and 95% confidence intervals. We adjusted for potential confounding and missing covariate data biases via inverse probability weights. We also used inverse probability weights to adjust for potential selection bias among a case group that included a disproportionate number of long-term survivors at enrollment.We observed 446 deaths during 24,267 person-months of follow-up (median follow-up: 28 months. Survival was shorter for cases who served before 1950, were deployed to World War II, or mixed and applied burning agents, with HRs between 1.58 and 2.57. Longer survival was associated with exposure to: paint, solvents, or petrochemical substances; local food not provided by the Armed Forces; or burning agents or Agent Orange in the field with HRs between 0.56 and 0.73.Although most military-related factors were not associated with survival, associations we observed with shorter survival are potentially important because of the large number of military veterans.

  1. Integrated MRI and [11 C]-PBR28 PET Imaging in Amyotrophic Lateral sclerosis.

    Science.gov (United States)

    Alshikho, Mohamad J; Zürcher, Nicole R; Loggia, Marco L; Cernasov, Paul; Reynolds, Beverly; Pijanowski, Olivia; Chonde, Daniel B; Izquierdo Garcia, David; Mainero, Caterina; Catana, Ciprian; Chan, James; Babu, Suma; Paganoni, Sabrina; Hooker, Jacob M; Atassi, Nazem

    2018-05-08

    To characterize [ 11 C]-PBR28 brain uptake using positron emission tomography (PET) in people with amyotrophic lateral sclerosis (ALS), and primary lateral sclerosis (PLS). We have previously shown increased [ 11 C]-PBR28 uptake in the precentral gyrus in a small group of ALS patients. Herein, we confirm our initial finding, study the longitudinal changes, and characterize the gray vs. white matter distribution of [ 11 C]-PBR28 uptake in a larger cohort of patients with ALS and PLS. Eighty-five participants including 53 ALS, 11 PLS and 21 healthy controls underwent integrated [ 11 C]-PBR28 PET-MR brain imaging. Patients were clinically assessed using the upper motor neuron burden (UMNB), and the revised ALS functional rating scale (ALSFRS-R). [ 11 C]-PBR28 uptake was quantified as standardized uptake value ratio (SUVR), and compared between groups. Cortical thickness, and fractional anisotropy were compared between groups and correlated with SUVR and the clinical data. [ 11 C]-PBR28 uptake and ALSFRS-R were compared longitudinally over six-month in ten ALS individuals. Whole brain voxel-wise, surface-based and region of interest analyses revealed increased [ 11 C]-PBR28 uptake in the precentral and paracentral gyri in ALS, and in the sub-cortical white matter for the same regions in PLS, compared to controls. The increase in [ 11 C]-PBR28 uptake co-localized and correlated with cortical thinning, reduced fractional anisotropy, increased mean diffusivity, and correlated with higher UMNB score. No significant changes were detected in [ 11 C]-PBR28 uptake over six-month despite clinical progression. Glial activation measured by in vivo [ 11 C]-PBR28 PET is increased in pathologically relevant regions in people with ALS and correlates with clinical measures. This article is protected by copyright. All rights reserved. © 2018 American Neurological Association.

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

    Science.gov (United States)

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

    2006-08-01

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

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

    Science.gov (United States)

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

    2016-12-01

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

  4. Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking parkinsonism, gaze palsy, aphasia, or dementia.

    Science.gov (United States)

    Nagao, Shigeto; Yokota, Osamu; Nanba, Reiko; Takata, Hiroshi; Haraguchi, Takashi; Ishizu, Hideki; Ikeda, Chikako; Takeda, Naoya; Oshima, Etsuko; Sakane, Katsuaki; Terada, Seishi; Ihara, Yuetsu; Uchitomi, Yosuke

    2012-12-15

    We report an autopsy case of progressive supranuclear palsy (PSP) that clinically showed only slowly progressive and symmetric upper motor neuron syndrome over a disease course of 12 years. A female patient initially exhibited dysarthria at the age of 65, followed by gait disturbance and dysphagia. Neurological examination at age 67 disclosed pseudobulbar palsy, spastic gait, hyperreflexia, and presence of bilateral Hoffmann and Babinski signs. However, muscle atrophy, weakness, evidence of denervation on electromyography, vertical gaze palsy, parkinsonism, gait freezing, aphasia, speech apraxia, or dementia was not noted throughout the course. She was clinically diagnosed as having motor neuron disease consistent with so-called primary lateral sclerosis. Pathological examination disclosed histopathological features of PSP, including argyrophilic and tau-positive tufted astrocytes, neurofibrillary tangles, coiled bodies, and thread-like processes in the motor cortex and superior frontal gyrus, and to a lesser degree, in the basal ganglia and brain stem nuclei. In addition, severe fibrillary gliosis was noted in the precentral gyrus and corticospinal tract, being consistent with upper motor neuron syndrome observed in this case. No TAR-DNA binding protein 43-positive lesion, FUS pathology, Bunina body, or Lewy body-like hyaline inclusion was noted in the motor cortex or lower motor neurons. These findings suggest that when tau pathology is prominent in the motor cortex but is minimal in the basal ganglia and brain stem nuclei, a PSP case can lack all classic clinical features of PSP and show only slowly progressive upper motor syndrome, consistent with clinical picture of primary lateral sclerosis. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Progression and effect of cognitive-behavioral changes in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Bock, Meredith; Duong, Y-Nhy; Kim, Anthony; Allen, Isabel; Murphy, Jennifer; Lomen-Hoerth, Catherine

    2017-12-01

    To prospectively evaluate the progression of cognitive-behavioral function in amyotrophic lateral sclerosis (ALS) and examine the association of cognitive-behavioral deficits with disease progression, patient quality of life (QOL), and caregiver burden. We evaluated cognitive-behavioral function using the Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen at enrollment and after 7 months in a cohort of patients with ALS. Paired t tests were used to evaluate the change in the 2 assessments. Linear regression and Kruskal-Wallis tests were applied to investigate how initial cognitive or behavioral status related to outcomes. The mean test-retest interval was 6.8 months (SD 1.6). Cognitive status of the study population (n = 49) overall did not change over the study period ( p = 0.06) despite progression of motor weakness ( p cognitive change. Patients initially classified as behaviorally normal showed increased behavioral problems over time ( t = -2.8, p = 0.009). Decline in cognitive (β = -1.3, p = 0.03) and behavioral (β = -0.76, p = 0.002) status predicted increasing caregiver burden. Behavioral abnormalities predicted decline in forced vital capacity and ALS Functional Rating Scale-Revised score ( p = 0.008, 0.012) in the study population and patient QOL in the most severely affected group ( t = 4.3, p = 0.003). Cognitive-behavioral change is a key aspect of disease heterogeneity in ALS. Executive function in ALS overall remains stable over 7 months as detected by an administered screening tool. However, patients may develop caregiver-reported behavioral symptoms in that time period. Screening for caregiver-reported symptoms has a particular utility in predicting future clinical decline, increased caregiver burden, and worsening patient QOL.

  6. Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes.

    Science.gov (United States)

    Feldman, Eva L; Boulis, Nicholas M; Hur, Junguk; Johe, Karl; Rutkove, Seward B; Federici, Thais; Polak, Meraida; Bordeau, Jane; Sakowski, Stacey A; Glass, Jonathan D

    2014-03-01

    The US Food and Drug Administration-approved trial, "A Phase 1, Open-Label, First-in-Human, Feasibility and Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1," is complete. Our overall objective was to assess the safety and feasibility of stem cell transplantation into lumbar and/or cervical spinal cord regions in amyotrophic lateral sclerosis (ALS) subjects. Preliminary results have been reported on the initial trial cohort of 12 ALS subjects. Here, we describe the safety and functional outcome monitoring results for the final trial cohort, consisting of 6 ALS subjects receiving 5 unilateral cervical intraspinal neural stem cell injections. Three of these subjects previously received 10 total bilateral lumbar injections as part of the earlier trial cohort. All injections utilized a novel spinal-mounted stabilization and injection device to deliver 100,000 neural stem cells per injection, for a dosing range up to 1.5 million cells. Subject assessments included detailed pre- and postsurgical neurological outcome measures. The cervical injection procedure was well tolerated and disease progression did not accelerate in any subject, verifying the safety and feasibility of cervical and dual-targeting approaches. Analyses on outcome data revealed preliminary insight into potential windows of stem cell biological activity and identified clinical assessment measures that closely correlate with ALS Functional Rating Scale-Revised scores, a standard assessment for ALS clinical trials. This is the first report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. This approach is feasible and well-tolerated, supporting future trial phases examining therapeutic dosing and efficacy. © 2014 Child Neurology Society/American Neurological Association.

  7. Mecasin treatment in patients with amyotrophic lateral sclerosis: study protocol for a randomized controlled trial.

    Science.gov (United States)

    Kim, Sungha; Kim, Jae Kyoun; Son, Mi Ju; Kim, Dongwoung; Song, Bongkeun; Son, Ilhong; Kang, Hyung Won; Lee, Jongdeok; Kim, Sungchul

    2018-04-13

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes paralysis of limb, swallowing, and breathing muscles. Riluzole, the Food and Drug Administration-approved drug for ALS, provides minimal benefit, prolonging patient life by only 2-3 months. Previous studies have found a neuro-protective and anti-neuroinflammatory effect of Mecasin, with retrospective studies providing suggestive evidence for a beneficial effect of Mecasin. The aim of this study was to develop a protocol to determine the proper dosage of Mecasin. This is a phase II-A, multi-center, randomized study with three arms. Thirty-six patients with ALS will be randomly assigned to one of three groups, each receiving the standard treatment with 100 mg of riluzole in addition to one of 1.6 g of Mecasin, 2.4 g of Mecasin, or a placebo. The Primary outcome is the Korean version of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised result after 12 weeks of treatment. Secondary outcomes include results of the Short Form Health Survey-8, Medical Research Council Scale, Visual Analogue Scale for Pain, Hamilton Rating Scale for Depression, Fatigue Severity Scale, Patient Global Impression of Change, pulmonary function test, forced expiratory volume in 1 s and its ratio to forced vital capacity, creatine kinase, and body weight. The frequencies of total adverse events and serious adverse events will be described and documented. The trial protocol has been approved by the Institutional Review Board of the Wonkwang University Gwangju and Sanbon Hospital (2016-5-4 and 2016-34-01, respectively). An Investigational New Drug status (30731) was granted by the Korea Food and Drug Administration. This trial will aim to identify the optimal dosage of Mecasin. Additionally, it will test the efficacy and safety of Mecasin in conjunction with standard treatment, riluzole, for alleviating the functional decline in patients with ALS. Korean National Clinical Trial Registry CRIS; KCT

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

    Directory of Open Access Journals (Sweden)

    Arturo Cardenas-Blanco

    2016-01-01

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

  9. 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.

  10. A validated HPLC assay to monitor riluzole plasma or serum concentrations in patients with amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van Kan, H. J. M.; Spieksma, M.; Groeneveld, G. J.; Toraño, J. Sastre; van den Berg, L. H.; Guchelaar, H. J.

    2004-01-01

    A specific, accurate and precise high-performance liquid chromatographic assay was developed for the determination of riluzole, a drug used to treat patients with amyotrophic lateral sclerosis. Samples were treated by extraction with dichloromethane followed by reversed-phase chromatography with

  11. 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

  12. 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

  13. 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

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

    NARCIS (Netherlands)

    Cudkowicz, Merit E.; van den Berg, Leonard H.; Shefner, Jeremy M.; Mitsumoto, Hiroshi; Mora, Jesus S.; Ludolph, Albert; Hardiman, Orla; Bozik, Michael E.; Ingersoll, Evan W.; Archibald, Donald; Meyers, Adam L.; Dong, Yingwen; Farwell, Wildon R.; Kerr, Douglas A.; Henderson, R.; Kiernan, M.; Mathers, S.; Vucic, S.; de Bleecker, J.; Robberecht, W.; Briemberg, H.; Genge, A.; Korngut, L.; Matte, G.; Shoesmith, C.; Zinman, L.; Camu, W.; Desnuelle, C.; Destee, A.; Meininger, V.; Pouget, J.; Grehl, T.; Grosskreutz, J.; Ludolph, A.; Meyer, T.; Petri, S.; Hardiman, O.; de Visser, M.; Voermans, N.; van den Berg, L.; de Rivera, F. J. R.; Gamez, J.; Carbonell, J. G.; Pardina, J. S. Mora; Povedano, M.; Persson, L.; Ronnevi, L.-O.; Al-Chalabi, A.; Morrison, K.; Shaw, P.

    2013-01-01

    In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of

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

    NARCIS (Netherlands)

    Cudkowicz, M.E.; Berg, L.H. van den; Shefner, J.M.; Mitsumoto, H.; Mora, J.S.; Ludolph, A.; Hardiman, O.; Bozik, M.E.; Ingersoll, E.W.; Archibald, D.; Meyers, A.L.; Dong, Y.; Farwell, W.R.; Kerr, D.A.; Voermans, N.C.; et al.,

    2013-01-01

    BACKGROUND: In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: Assessed with [11C]-PBR28

    Directory of Open Access Journals (Sweden)

    Nicole R. Zürcher

    2015-01-01

    Full Text Available Evidence from human post mortem, in vivo and animal model studies implicates the neuroimmune system and activated microglia in the pathology of amyotrophic lateral sclerosis. The study aim was to further evaluate in vivo neuroinflammation in individuals with amyotrophic lateral sclerosis using [11C]-PBR28 positron emission tomography. Ten patients with amyotrophic lateral sclerosis (seven males, three females, 38–68 years and ten age- and [11C]-PBR28 binding affinity-matched healthy volunteers (six males, four females, 33–65 years completed a positron emission tomography scan. Standardized uptake values were calculated from 60 to 90 min post-injection and normalized to whole brain mean. Voxel-wise analysis showed increased binding in the motor cortices and corticospinal tracts in patients with amyotrophic lateral sclerosis compared to healthy controls (pFWE < 0.05. Region of interest analysis revealed increased [11C]-PBR28 binding in the precentral gyrus in patients (normalized standardized uptake value = 1.15 compared to controls (1.03, p < 0.05. In patients those values were positively correlated with upper motor neuron burden scores (r = 0.69, p < 0.05, and negatively correlated with the amyotrophic lateral sclerosis functional rating scale (r = –0.66, p < 0.05. Increased in vivo glial activation in motor cortices, that correlates with phenotype, complements previous histopathological reports. Further studies will determine the role of [11C]-PBR28 as a marker of treatments that target neuroinflammation.

  1. Multiple sclerosis: Left advantage for auditory laterality in dichotic tests of central auditory processing and relationship of psychoacoustic tests with the Multiple Sclerosis Disability Scale-EDSS.

    Science.gov (United States)

    Peñaloza López, Yolanda Rebeca; Orozco Peña, Xóchitl Daisy; Pérez Ruiz, Santiago Jesús

    2018-04-03

    To evaluate the central auditory processing disorders in patients with multiple sclerosis, emphasizing auditory laterality by applying psychoacoustic tests and to identify their relationship with the Multiple Sclerosis Disability Scale (EDSS) functions. Depression scales (HADS), EDSS, and 9 psychoacoustic tests to study CAPD were applied to 26 individuals with multiple sclerosis and 26 controls. Correlation tests were performed between the EDSS and psychoacoustic tests. Seven out of 9 psychoacoustic tests were significantly different (P<.05); right or left (14/19 explorations) with respect to control. In dichotic digits there was a left-ear advantage compared to the usual predominance of RDD. There was significant correlation in five psychoacoustic tests and the specific functions of EDSS. The left-ear advantage detected and interpreted as an expression of deficient influences of the corpus callosum and attention in multiple sclerosis should be investigated. There was a correlation between psychoacoustic tests and specific EDSS functions. Copyright © 2018 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. 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

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

    Science.gov (United States)

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

    2016-01-01

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

  4. 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.

  5. Altered cortical activation during action observation in amyotrophic lateral sclerosis patients: a parametric functional MRI study

    International Nuclear Information System (INIS)

    Li, Haiqing; Li, Yuxin; Yin, Bo; Tang, Weijun; Yu, Xiangrong; Geng, Daoying; Chen, Yan; Huang, Weiyuan; Zhang, Biyun

    2015-01-01

    To investigate functional cerebral abnormalities in patients with amyotrophic lateral sclerosis (ALS) using functional magnetic resonance imaging (fMRI) during action observation. Thirty patients with ALS and 30 matched healthy controls underwent fMRI with an experimental paradigm while observing a video of repetitive flexion-extension of the fingers at three frequency levels or three complexity levels, alternated with periods of a static hand. A parametric analysis was applied to determine the effects of each of the two factors. Action observation activated similar neural networks as the research on execution of action in the ALS patients and healthy subjects in several brain regions related to the mirror-neuron system (MNS). In the ALS patients, in particular, the dorsal lateral premotor cortex (dPMC), inferior parietal gyrus (IPG), and SMA, were more activated compared with the activation in the controls. Increased activation within the primary motor cortex (M1), dPMC, inferior frontal gyrus (IFG), and superior parietal gyrus (SPG) mainly correlated with hand movement frequency/complexity in the videos in the patients compared with controls. The findings indicated an ongoing compensatory process occurring within the higher order motor-processing system of ALS patients, likely to overcome the loss of function. (orig.)

  6. Altered cortical activation during action observation in amyotrophic lateral sclerosis patients: a parametric functional MRI study

    Energy Technology Data Exchange (ETDEWEB)

    Li, Haiqing; Li, Yuxin; Yin, Bo; Tang, Weijun; Yu, Xiangrong; Geng, Daoying [Huashan Hospital, Department of Radiology, Fudan University, Shanghai (China); Chen, Yan [Fudan University, Department of Neurology, Huashan Hospital, Shanghai (China); Huang, Weiyuan [People' s Hospital of Hainan Province, Department of Radiology, Haikou, Hainan Province (China); Zhang, Biyun [Nanjing University of Traditional Chinese Medicine, Department of radiotherapy, Affiliated Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing (China)

    2015-09-15

    To investigate functional cerebral abnormalities in patients with amyotrophic lateral sclerosis (ALS) using functional magnetic resonance imaging (fMRI) during action observation. Thirty patients with ALS and 30 matched healthy controls underwent fMRI with an experimental paradigm while observing a video of repetitive flexion-extension of the fingers at three frequency levels or three complexity levels, alternated with periods of a static hand. A parametric analysis was applied to determine the effects of each of the two factors. Action observation activated similar neural networks as the research on execution of action in the ALS patients and healthy subjects in several brain regions related to the mirror-neuron system (MNS). In the ALS patients, in particular, the dorsal lateral premotor cortex (dPMC), inferior parietal gyrus (IPG), and SMA, were more activated compared with the activation in the controls. Increased activation within the primary motor cortex (M1), dPMC, inferior frontal gyrus (IFG), and superior parietal gyrus (SPG) mainly correlated with hand movement frequency/complexity in the videos in the patients compared with controls. The findings indicated an ongoing compensatory process occurring within the higher order motor-processing system of ALS patients, likely to overcome the loss of function. (orig.)

  7. Multi-parametric spinal cord MRI as potential progression marker in amyotrophic lateral sclerosis.

    Science.gov (United States)

    El Mendili, Mohamed-Mounir; Cohen-Adad, Julien; Pelegrini-Issac, Mélanie; Rossignol, Serge; Morizot-Koutlidis, Régine; Marchand-Pauvert, Véronique; Iglesias, Caroline; Sangari, Sina; Katz, Rose; Lehericy, Stéphane; Benali, Habib; Pradat, Pierre-François

    2014-01-01

    To evaluate multimodal MRI of the spinal cord in predicting disease progression and one-year clinical status in amyotrophic lateral sclerosis (ALS) patients. After a first MRI (MRI1), 29 ALS patients were clinically followed during 12 months; 14/29 patients underwent a second MRI (MRI2) at 11±3 months. Cross-sectional area (CSA) that has been shown to be a marker of lower motor neuron degeneration was measured in cervical and upper thoracic spinal cord from T2-weighted images. Fractional anisotropy (FA), axial/radial/mean diffusivities (λ⊥, λ//, MD) and magnetization transfer ratio (MTR) were measured within the lateral corticospinal tract in the cervical region. Imaging metrics were compared with clinical scales: Revised ALS Functional Rating Scale (ALSFRS-R) and manual muscle testing (MMT) score. At MRI1, CSA correlated significantly (Pleg ALFSRS-R scores. One year after MRI1, CSA predicted (Pleg ALSFRS-R subscore. From MRI1 to MRI2, significant changes (PDTI metrics predicted ALS disease progression. Cord atrophy was a better biomarker of disease progression than diffusion and MTR. Our study suggests that multimodal MRI could provide surrogate markers of ALS that may help monitoring the effect of disease-modifying drugs.

  8. 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

  9. Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology.

    Science.gov (United States)

    Beard, John D; Engel, Lawrence S; Richardson, David B; Gammon, Marilie D; Baird, Coleen; Umbach, David M; Allen, Kelli D; Stanwyck, Catherine L; Keller, Jean; Sandler, Dale P; Schmidt, Silke; Kamel, Freya

    2016-05-01

    Factors underlying a possible excess of amyotrophic lateral sclerosis (ALS) among military veterans remain unidentified. Limitations of previous studies on this topic include reliance on ALS mortality as a surrogate for ALS incidence, low statistical power, and sparse information on military-related factors. We evaluated associations between military-related factors and ALS using data from a case-control study of U.S. military veterans. From 2005 to 2010, we identified medical record-confirmed ALS cases via the National Registry of Veterans with ALS and controls via the Veterans Benefits Administration's Beneficiary Identification and Records Locator System database. In total, we enrolled 621 cases and 958 frequency-matched controls in the Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis study. We collected information on military service and deployments and 39 related exposures. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We used inverse probability weighting to adjust for potential bias from confounding, missing covariate data, and selection arising from a case group that disproportionately included long-term survivors and a control group that may or may not differ from U.S. military veterans at large. The odds of ALS did not differ for veterans of the Air Force, Army, Marines, and Navy. We found higher odds of ALS for veterans whose longest deployment was World War II or the Korean War and a positive trend with total years of all deployments (OR=1.27; 95% CI: 1.06, 1.52). ALS was positively associated with exposure to herbicides for military purposes, nasopharyngeal radium, personal pesticides, exhaust from heaters or generators, high-intensity radar waves, contaminated food, explosions within one mile, herbicides in the field, mixing and application of burning agents, burning agents in the field, and Agent Orange in the field, with ORs between 1.50 and 7

  10. 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

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

    LENUS (Irish Health Repository)

    Byrne, Susan

    2012-02-01

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

  12. Climatic factors associated with amyotrophic lateral sclerosis: a spatial analysis from Taiwan.

    Science.gov (United States)

    Tsai, Ching-Piao; Tzu-Chi Lee, Charles

    2013-11-01

    Few studies have assessed the spatial association of amyotrophic lateral sclerosis (ALS) incidence in the world. The aim of this study was to identify the association of climatic factors and ALS incidence in Taiwan. A total of 1,434 subjects with the primary diagnosis of ALS between years 1997 and 2008 were identified in the national health insurance research database. The diagnosis was also verified by the national health insurance programme, which had issued and providing them with "serious disabling disease (SDD) certificates". Local indicators of spatial association were employed to investigate spatial clustering of age-standardised incidence ratios in the townships of the study area. Spatial regression was utilised to reveal any association of annual average climatic factors and ALS incidence for the 12-year study period. The climatic factors included the annual average time of sunlight exposure, average temperature, maximum temperature, minimum temperature, atmospheric pressure, rainfall, relative humidity and wind speed with spatial autocorrelation controlled. Significant correlations were only found for exposure to sunlight and rainfall and it was similar in both genders. The annual average of the former was found to be negatively correlated with ALS, while the latter was positively correlated with ALS incidence. While accepting that ALS is most probably multifactorial, it was concluded that sunlight deprivation and/or rainfall are associated to some degree with ALS incidence in Taiwan.

  13. SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Le Ber, Isabelle; Camuzat, Agnès; Guerreiro, Rita; Bouya-Ahmed, Kawtar; Bras, Jose; Nicolas, Gael; Gabelle, Audrey; Didic, Mira; De Septenville, Anne; Millecamps, Stéphanie; Lenglet, Timothée; Latouche, Morwena; Kabashi, Edor; Campion, Dominique; Hannequin, Didier; Hardy, John; Brice, Alexis

    2013-11-01

    Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. Primary care or referral center. An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

  14. 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.

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

    Science.gov (United States)

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

    2015-10-01

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

  16. TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update.

    Science.gov (United States)

    Lattante, Serena; Rouleau, Guy A; Kabashi, Edor

    2013-06-01

    Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau-negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance, and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here have been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/TARDBP, www.lovd.nl/FUS. © 2013 Wiley Periodicals, Inc.

  17. 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.

  18. Physician perceptions about living organ donation in patients with Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Ansari, S; Bromberg, M B; Gibson, S B

    2017-09-01

    Patients with Amyotrophic Lateral Sclerosis (ALS) have expressed desire to become living organ donors but are unable to do so with current organ donation policies. Our objective is to assess ALS patient's interest in organ donation, and perceived concerns of this practice by ALS neurologists. An electronic survey was administered to ALS neurologists across the United States regarding living organ donation in ALS patients prior to respiratory failure. 52 complete responses were received from 121 invites. 67% (35/52) of neurologists expressed no concerns about living organ donation in ALS patients, and 33% had concerns. The concerns related to respiratory failure, anesthesia exposure and renal dysfunction. With their concerns addressed, 71% of neurologists reported that they would endorse living organ donation. 49% of neurologists reported being asked by a patient for information regarding living organ donation. ALS neurologists felt that 22.8% of ALS patients (median 19%) would be interested in learning more about organ donation, while only 6% of neurologists broach this subject with their patients. Our results indicate that 1 in every 4 ALS patients may be interested in exploring options for living organ donation, and this topic is not routinely addressed by ALS clinics. These results indicate an unexplored area of patient interest. To honor a patient's wishes to donate, the transplant community will have to accommodate living organ donation from terminally ill patients, and address neurologist concerns. Such a practice could benefit two groups of patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. 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.

  20. 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.

  1. Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice.

    Science.gov (United States)

    Del Signore, Steven J; Amante, Daniel J; Kim, Jinho; Stack, Edward C; Goodrich, Sarah; Cormier, Kerry; Smith, Karen; Cudkowicz, Merit E; Ferrante, Robert J

    2009-04-01

    Recent evidence suggests that transcriptional dysregulation may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). The histone deacetylase inhibitor, sodium phenylbutyrate (NaPB), is neuroprotective and corrects aberrant gene transcription in ALS mice and has recently been shown to be safe and tolerable in ALS patients while improving hypoacetylation. Since many patients are already on riluzole, it is important to ensure that any proposed therapy does not result in negative synergy with riluzole. The combined treatment of riluzole and NaPB significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice beyond either agent alone. Combination therapy increased survival by 21.5%, compared to the separate administration of riluzole (7.5%) and NaPB (12.8%), while improving both body weight loss and grip strength. The data show that the combined treatment was synergistic. In addition, riluzole/NaPB treatment ameliorated gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Riluzole/NaPB administration increased acetylation at H4 and increased NF-kappaB p50 translocation to the nucleus in G93A mice, consistent with a therapeutic effect. These data suggest that NaPB may not interfere with the pharmacologic action of riluzole in ALS patients.

  2. Early-onset alopecia and amyotrophic lateral sclerosis: a cohort study.

    Science.gov (United States)

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

    2013-10-01

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

  3. Using technology to improve access to specialist care in amyotrophic lateral sclerosis: A systematic review.

    Science.gov (United States)

    Hobson, Esther V; Baird, Wendy O; Cooper, Cindy L; Mawson, Sue; Shaw, Pamela J; Mcdermott, Christopher J

    2016-01-01

    Our objective was to review the evidence for using technology to improve access to specialist care for patients with amyotrophic lateral sclerosis (ALS) and their carers. Medline, Google Scholar and the Cochrane library were searched for articles describing technology that enabled clinical care of patients with ALS or their carers where the patient/carer and clinician were not in the same location. Two applications were identified: telemedicine to facilitate video conferencing as an alternative to outpatient consultations and telehealth monitoring for patients with respiratory failure. One randomized controlled trial using telehealth in patients with respiratory failure including 22 patients with ALS was identified. While rates of hospitalization were reduced, overall mortality was unchanged and there were too few patients with ALS in the study to detect significant benefit. In conclusion, there is limited evidence to support the use of telemedicine or telehealth in the care of patients with ALS. Future research needs to develop an understanding of the key beneficial aspects of the traditional specialist ALS service and how these factors could be delivered using technology. Successful evaluation and implementation of technologies to facilitate access to specialist care will only be possible if all the relevant impacts of an intervention are understood and measured.

  4. A prospective pilot study measuring muscle volumetric change in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Jenkins, Thomas M; Burness, Christine; Connolly, Daniel J; Rao, D Ganesh; Hoggard, Nigel; Mawson, Susan; McDermott, Christopher J; Wilkinson, Iain D; Shaw, Pamela J

    2013-09-01

    Our objective was to investigate the potential of muscle volume, measured with magnetic resonance (MR), as a biomarker to quantify disease progression in patients with amyotrophic lateral sclerosis (ALS). In this longitudinal pilot study, we first sought to determine the stability of volumetric muscle MR measurements in 11 control subjects at two time-points. We assessed feasibility of detecting atrophy in four patients with ALS, followed at three-month intervals for 12 months. Muscle power and MR volume were measured in thenar eminence (TEm), first dorsal interosseous (1DIO), tibialis anterior (TA) and tongue. Changes over time were assessed using linear regression models and t-tests. Results demonstrated that, in controls, no volumetric MR changes were seen (mean volume variation in all muscles 0.1). In patients, between-subject heterogeneity was identified. Trends for volume loss were found in TEm (mean, - 26.84%, p = 0.056) and TA (- 8.29%, p = 0.077), but not in 1DIO (- 18.47%, p = 0.121) or tongue (< 5%, p = 0.367). In conclusion, volumetric muscle MR appears a stable measure in controls, and progressive volume loss was demonstrable in individuals with ALS in whom clinical weakness progressed. In this small study, subclinical atrophy was not demonstrable using muscle MR. Clinico-radiological discordance between muscle weakness and MR atrophy could reflect a contribution of upper motor neuron pathology.

  5. Cell Death-Autophagy Loop and Glutamate-Glutamine Cycle in Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Shu Yuan

    2017-07-01

    Full Text Available Although we know that amyotrophic lateral sclerosis (ALS is correlated with the glutamate-mediated corticomotor neuronal hyperexcitability, detailed ALS pathology remains largely unexplained. While a number of drugs have been developed, no cure exists so far. Here, we propose a hypothesis of neuronal cell death—incomplete autophagy positive-feedback loop—and summarize the role of the neuron-astrocyte glutamate-glutamine cycle in ALS. The disruption of these two cycles might ideally retard ALS progression. Cerebrovascular injuries (such as multiple embolization sessions and strokes induce neuronal cell death and the subsequent autophagy. ALS impairs autophagosome-lysosome fusion and leads to magnified cell death. Trehalose rescues this impaired fusion step, significantly delaying the onset of the disease, although it does not affect the duration of the disease. Therefore, trehalose might be a prophylactic drug for ALS. Given that a major part of neuronal glutamate is converted from glutamine through neuronal glutaminase (GA, GA inhibitors may decrease the neuronal glutamate accumulation, and, therefore, might be therapeutic ALS drugs. Of these, Ebselen is the most promising one with strong antioxidant properties.

  6. Power Wheelchair Use in Persons With Amyotrophic Lateral Sclerosis: Changes Over Time.

    Science.gov (United States)

    Ward, Amber Lea; Hammond, Sara; Holsten, Scott; Bravver, Elena; Brooks, Benjamin Rix

    2015-01-01

    The objectives of this study were to survey persons with Amyotrophic Lateral Sclerosis (ALS) at 1 and 6 months after receiving power wheelchairs to determine long-term use, comfort, and function as well as the power wheelchair's impact on daily tasks and quality of life. A 33-question survey and Psychosocial Impact of Assistive Devices Scale (PIADS) were sent 1 month after getting a new power wheelchair; a follow-up survey was sent at 6 months. Based on satisfaction and feature use survey results, at 1 month, 81% of users found the power wheelchair overall comfort to be high, 88% found their overall mobility to be improved, and 95% found it easy to use. Their quality of life increased and pain decreased at 1 and 6 months. According to the PIADS, the power wheelchair gave users increased ability to participate and sense of competence. This study has important results for the ALS community, as it is the first to assess power wheelchair users at 1 and 6 months after power wheelchair procurement. The results demonstrate the impact the power wheelchair has on mobility, psychosocial issues, functional abilities, and quality of life for a person with ALS.

  7. Interplay of upper and lower motor neuron degeneration in amyotrophic lateral sclerosis.

    Science.gov (United States)

    de Carvalho, Mamede; Poliakov, Artiom; Tavares, Cristiano; Swash, Michael

    2017-11-01

    We studied motor unit recruitment to test a new method to identify motor unit firing rate (FR) variability. We studied 68 ALS patients, with and without upper neuron signs (UMN) in lower limbs, 24 patients with primary lateral sclerosis (PLS), 13 patients with spinal cord lesion and 39 normal subjects. All recordings were made from tibialis anterior muscles of normal strength. Subjects performed a very slight contraction in order to activate 2 motor units in each recording. 5-7 motor unit pairs were recorded in each subject. Mean consecutive differences (MCD) were calculated for each pair of potentials. The mean MCD for each muscle was estimated as the mean from the total number of pairs recorded. Ap valuemotor unit in a pair of units was markedly reduced in PLS, and in subjects with spinal cord lesions. These results support a lower threshold and reduced FR fluctuation in spinal motor neurons of spastic patients. This method can be developed for detection of UMN lesions. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Lavoisier Leite Neto

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

  9. [Evaluation and treatment of dysphagia in amyotrophic lateral sclerosis and Parkinson's disease].

    Science.gov (United States)

    Yamamoto, Toshiyuki

    2011-11-01

    As both amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) exhibit a variety of patterns of dysphagia, appropriate symptomatic treatment is provided after evaluation of swallowing function through videofluoroscopic examination of swallowing. In ALS, disease progression is rapid, therefore, respiratory function, swallowing function and nutritional status should be evaluated regularly. When the oral or pharyngeal stage of swallowing are affected early in dysphagia, adjusting swallowing volume and varying consistency can be beneficial in ALS. When all stages of swallowing are impaired in ALS, such complications as pneumonia, dehydration and malnutrition, are observed. In such patients, it is necessary to consider an alternative to oral dietary intake. In PD, dysphagia is not necessarily associated with severity of parkinsonism and can appear at any time during the course of the disease. Dysphagia in PD can occur at any stage of swallowing and frequently accompanies multiple abnormalities. In particular, aspiration is an important risk factor for pneumonia in PD. The effect of L-dopa treatment for dysphagia is often insufficient; however, this treatment remains the first choice because dysphagia is exacerbated during off state. Rehabilitation for dysphagia in PD has also some effect.

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

    Science.gov (United States)

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

    2012-10-16

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

  11. Is there a link between physical activity and Amyotrophic Lateral Sclerosis?

    Directory of Open Access Journals (Sweden)

    Giuseppe La Torre

    2015-12-01

    Full Text Available The Amyotrophic Lateral Sclerosis (ALS is a chronic and progressive neuro-degenerative pathology that starts in adult age and usually leads patients to death for respiratory distress after 3 years from the onset of symptoms In some studies, vigorous and continuous physical activity due to heavy working activity and sport is associated with ALS. On the other hand other studies are against this association. A study carried out in Europe found overall physical activity is associated with reduced odds of having ALS (OR=0.65, 95% CI=0.48-0.89, and the same protective factor is seen for work-related physical activity (OR=0.56, 95% CI=0.36-0.87 and organized sports (OR=0.49, 95% CI=0.32-0.75.A recent literature review found that football/soccer may be considered as a possible risk factor for ALS (level C and there is a strong need for further research that must take into account the numerous confounding factors that could be present in this field. However only well conducted observational studies, such as cohort and case-control studies, carried out with the same design in different countries could give a final answer to this suspected but still unconfirmed association

  12. A case of celiac disease with neurologic manifestations misdiagnosed as amyotrophic lateral sclerosis

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    Hyoju Ham

    2017-10-01

    Full Text Available Celiac disease (CD is an immune-mediated enteropathy and is a rare disease in Asia, including in Korea. However, the ingestion of wheat products, which can act as a precipitating factor of CD, has increased rapidly. CD is a common cause of malabsorption, but many patients can present with various atypical manifestations as first presented symptoms, including anemia, osteopenia, infertility, and neurological symptoms. Thus, making a diagnosis is challenging. We report a case of CD that mimicked amyotrophic lateral sclerosis (ALS. The patient was a sexagenary man with a history of progressive motor weakness for 2 years. He was highly suspected as having ALS. During evaluation of his neurological symptoms, esophagogastroduodenoscopy (EGD was performed because he had experienced loose stools and weight loss for the previous 7 months. On EGD, the duodenal mucosa appeared smooth. A biopsy revealed severe lymphoplasma cell infiltration with flattened villi. His serum endomysial antibody (immunoglobulin A titer was 1:160 (reference, <1:40. Finally, he was diagnosed as having CD, and a gluten-free diet was immediately begun. At a 4-month follow-up, his weight and the quality of his stool had improved gradually, and the neurological manifestations had not progressed.

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

    Science.gov (United States)

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

    2007-07-11

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

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

    LENUS (Irish Health Repository)

    Byrne, Susan

    2010-11-03

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

  15. 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.

  16. 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

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

    International Nuclear Information System (INIS)

    Takahashi, Ryosuke; Imai, Terukuni; Sadashima, Hiromichi; Matsumoto, Sadayuki; Yamamoto, Toru; Kusaka, Hirobumi; Yamasaki, Masahiro; Maya, Kiyomi; Tanabe, Masaya

    1989-01-01

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

  18. 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.

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    Viktor Hartung

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

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

    Science.gov (United States)

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

    2009-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Mathew eStaios

    2013-05-01

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

  3. 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.

  4. 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.

  5. Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Okada, Masamitsu; Yamashita, Satoshi; Ueyama, Hidetsugu; Ishizaki, Masatoshi; Maeda, Yasushi; Ando, Yukio

    2018-06-01

    Oxidative stress has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone, a free radical scavenger, was approved as a therapeutic drug for ALS in 2015 in Japan. A phase 3 clinical trial demonstrated a smaller decline in ALS functional scale scores compared with placebo. However, the long-term effects of edaravone on ALS patients remain unclear. This study aimed to retrospectively investigate the long-term effects of edaravone on the survival of ALS patients. We retrospectively analyzed 27 consecutive patients with ALS who were treated with edaravone and 30 consecutive ALS patients who were not treated with edaravone between 2010 and 2016. The differences of ALSFRS-R scores from baseline to 6 months was significantly reduced in the edaravone group, compared to the control group. The changes in serum creatinine, as a possible marker of ALS severity, from baseline to 6 and 12 months were significantly improved in the edaravone group, compared to the control group. The survival rate was significantly improved in the edaravone group compared with control patients. Our retrospective single-center analysis suggests slower progression and better prognosis of ALS patients with edaravone treatment. Further investigation, including prospective multicenter analysis, is warranted to confirm the usefulness of edaravone for a better prognosis of ALS.

  6. Finding Inhibitors of Mutant Superoxide Dismutase-1 for Amyotrophic Lateral Sclerosis Therapy from Traditional Chinese Medicine

    Directory of Open Access Journals (Sweden)

    Hung-Jin Huang

    2014-01-01

    Full Text Available Superoxide dismutase type 1 (SOD1 mutations cause protein aggregation and decrease protein stability, which are linked to amyotrophic lateral sclerosis (ALS disease. This research utilizes the world’s largest traditional Chinese medicine (TCM database to search novel inhibitors of mutant SOD1, and molecular dynamics (MD simulations were used to analyze the stability of protein that interacted with docked ligands. Docking results show that hesperidin and 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG have high affinity to mutant SOD1 and then dopamine. For MD simulation analysis, hesperidin and THSG displayed similar value of RMSD with dopamine, and the migration analysis reveals stable fluctuation at the end of MD simulation time. Interestingly, distance between the protein and ligand has distinct difference, and hesperidin changes the position from initial binding site to the other place. In flexibility of residues analysis, the secondary structure among all complexes does not change, indicating that the structure are not affect ligand binding. The binding poses of hesperidin and THSG are similar to dopamine after molecular simulation. Our result indicated that hesperidin and THSG might be potential lead compound to design inhibitors of mutant SOD1 for ALS therapy.

  7. Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center.

    Science.gov (United States)

    Chadi, Gerson; Maximino, Jessica Ruivo; Jorge, Frederico Mennucci de Haidar; Borba, Fabrício Castro de; Gilio, Joyce Meire; Callegaro, Dagoberto; Lopes, Camila Galvão; Santos, Samantha Nakamura Dos; Rebelo, Gabriela Natania Sales

    2017-05-01

    To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients.

  8. A cognitive brain-computer interface for patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Hohmann, M R; Fomina, T; Jayaram, V; Widmann, N; Förster, C; Just, J; Synofzik, M; Schölkopf, B; Schöls, L; Grosse-Wentrup, M

    2016-01-01

    Brain-computer interfaces (BCIs) are often based on the control of sensorimotor processes, yet sensorimotor processes are impaired in patients suffering from amyotrophic lateral sclerosis (ALS). We devised a new paradigm that targets higher-level cognitive processes to transmit information from the user to the BCI. We instructed five ALS patients and twelve healthy subjects to either activate self-referential memories or to focus on a process without mnemonic content while recording a high-density electroencephalogram (EEG). Both tasks are designed to modulate activity in the default mode network (DMN) without involving sensorimotor pathways. We find that the two tasks can be distinguished after only one experimental session from the average of the combined bandpower modulations in the theta- (4-7Hz) and alpha-range (8-13Hz), with an average accuracy of 62.5% and 60.8% for healthy subjects and ALS patients, respectively. The spatial weights of the decoding algorithm show a preference for the parietal area, consistent with modulation of neural activity in primary nodes of the DMN. © 2016 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2017-12-01

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

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

    Science.gov (United States)

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

    2007-01-01

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

  11. 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.

  12. Impact of disease, cognitive and behavioural factors on caregiver outcome in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Watermeyer, Tamlyn J; Brown, Richard G; Sidle, Katie C L; Oliver, David J; Allen, Christopher; Karlsson, Joanna; Ellis, Cathy; Shaw, Christopher E; Al-Chalabi, Ammar; Goldstein, Laura H

    2015-01-01

    Up to 50% of patients with amyotrophic lateral sclerosis (ALS) show mild to moderate cognitive-behavioural change alongside their progressive functional impairment. This study examines the relative impact of patients' disease symptoms, behavioural change and current executive function and social cognition abilities on psychosocial outcomes in spouse caregivers of people with ALS. Thirty-five spouse caregivers rated their own levels of depression and anxiety, subjective burden and marital satisfaction. Caregivers also rated their partner's everyday behaviour. The patients were assessed for disease severity and cognitive function, with composite scores derived for executive function and social cognition. Regression analyses revealed that caregiver burden was predicted by the severity of patients' limb involvement and behavioural problems. Depression was predicted by patients' limb involvement, while behavioural problems and patient age predicted caregiver anxiety. Current marital satisfaction was predicted by patient behavioural problems beyond the level of pre-illness marital satisfaction. In conclusion, the study highlights the potential impact of ALS patients' functional impairment and behavioural change on ALS caregivers' psychosocial functioning. Clinical communication with ALS families should emphasise both physical and psychological challenges presented by the disease.

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

    Science.gov (United States)

    Maessen, Maud; Veldink, Jan H; Onwuteaka-Philipsen, Bregje D; Hendricks, Henk T; Schelhaas, Helenius J; Grupstra, Hepke F; van der Wal, Gerrit; van den Berg, Leonard H

    2014-10-01

    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 patients filled out structured questionnaires every 3 months until death and the results were correlated with EAS. Thirty-one percent of the patients requested EAS, 69% of whom eventually died as a result of EAS (22% of all patients). Ten percent died during continuous deep sedation; only one of them had explicitly requested death to be hastened. Of the patients who requested EAS, 86% considered the health care to be good or excellent, 16% felt depressed, 45% experienced loss of dignity and 42% feared choking. These percentages do not differ from the number of patients who did not explicitly request EAS. The frequency of consultations of professional caregivers and availability of appliances was similar in both groups. Our findings do not support continuous deep sedation being used as a substitute for EAS. In this prospective study, no evidence was found for a relation between EAS and the quality and quantity of care received, quality of life and symptoms of depression in patients with ALS. Our study does not support the notion that unmet palliative care needs are related to EAS.

  14. 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.

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

    Science.gov (United States)

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

    2018-05-01

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

  16. 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.

  17. Voluntary Cough Airflow Differentiates Safe versus Unsafe Swallowing in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Plowman, Emily K.; Watts, Stephanie A.; Robison, Raele; Tabor, Lauren; Dion, Charles; Gaziano, Joy; Vu, Tuan; Gooch, Clifton

    2016-01-01

    Dysphagia and aspiration are prevalent in amyotrophic lateral sclerosis (ALS) and contribute to malnutrition, aspiration pneumonia and death. Early detection of at risk individuals is critical to ensure maintenance of safe oral intake and optimal pulmonary function. We therefore aimed to determine the discriminant ability of voluntary cough airflow measures in detecting penetration/aspiration status in ALS patients. Seventy individuals with ALS (El-Escorial criteria) completed voluntary cough spirometry testing and underwent a standardized videofluoroscopic swallowing evaluation (VFSE). A rater blinded to aspiration status derived six objective measures of voluntary cough airflow and evaluated airway safety using the Penetration Aspiration Scale (PAS). A between groups ANOVA (safe vs. unsafe swallowers) was conducted and sensitivity, specificity, area under the curve (AUC) and likelihood ratios were calculated. VFSE analysis revealed 24 penetrator/aspirators (PAS ≥3) and 46 non-penetrator/aspirators (PAS ≤2). Cough volume acceleration (CVA), peak expiratory flow rise time (PEFRT), and peak expiratory flow rate (PEFR) were significantly different between airway safety groups (p 76ms had sensitivities of 91.3%, 82.6% and 73.9% respectively and specificities of 82.2%, 73.9%, and 78.3% for identifying ALS penetrator/aspirators. Voluntary cough airflow measures identified ALS patients at risk for penetration/aspiration and may be a valuable screening tool with high clinical utility. PMID:26803772

  18. 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.

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

    Science.gov (United States)

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

    2017-06-01

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

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

    Science.gov (United States)

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

    2018-03-19

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

  2. 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.

  3. [Health-related quality of life in patients with amyotrophic lateral sclerosis].

    Science.gov (United States)

    Sánchez-López, C R; Perestelo-Pérez, L; Ramos-Pérez, C; López-Bastida, J; Serrano-Aguilar, P

    2014-01-01

    Progressive deterioration in patients with amyotrophic lateral sclerosis (ALS) has a major impact on their health-related quality of life (HRQOL). The objectives of this study are to evaluate HRQOL in a sample of patients diagnosed with ALS and estimate the predictive capability of a set of sociodemographic variables for the different scales covered by a general health survey. A total of 63 patients diagnosed with ALS were assessed using a sociodemographic questionnaire and the SF-36 general health survey. The sociodemographic variables studied were sex, age, presence of a caregiver, employment status, and time from diagnosis of disease. The SF-36 survey shows positive correlations between the different scales composing it, which proves its reliability. The mean scores obtained for each of the SF-36 scales were higher in men than in women, although the only statistically significant difference was for the Physical Role scale. The lowest age range (less than 56 years) presented the highest mean scores for most of these dimensions. Most of the variance in the test is explained by the variable 'presence of caregiver'. The SF-36 health survey has been confirmed as a valid and useful tool for evaluating HRQOL in ALS patients, and it discriminates between patients in different states of health according to their level of dependency. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  4. 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.

  5. [Unexpected treatable dyspnea caused by intratracheal granuloma in an amyotrophic lateral sclerosis patient with mechanical ventilation].

    Science.gov (United States)

    Ishida, Shimon; Kimura, Fumiharu; Hosokawa, Takafumi; Satoh, Toshihiko; Furutama, Daisuke; Sugino, Masakazu

    2007-09-01

    Respiratory insufficiency is a problem that develops in nearly all people diagnosed with amyotrophic lateral sclerosis (ALS). A 46-year-old man with ALS, who had been in a bedridden state with tracheal ventilation support, complained of faintness and dyspnea. The airway pressure of the ventilator had increased, and bleeding from the trachea had occurred several times. A fiberoptic bronchoscopy showed granulation located on the anterior wall of the trachea and severe airway obstruction of the tracheostomy tube. Although a long tracheostomy tube had been intubated for the initial management of the tracheal granulation, a tumor on the posterior tracheal wall had relapsed and occluded the tracheal lumen. A self-expandable metallic airway stent was placed into the tracheal stenosis. After stenting, his symptoms of dyspnea and syncope imploved, and the increased airway pressure of the ventilator was normalized. We speculated that the tracheal granuloma had occurred due to a tracheal mucosal injury related to endotracheal suctioning. We should pay attention to complaints of dyspnea in ALS patients with tracheostomy and make a careful consideration to airway care including suction management.

  6. Classification of amyotrophic lateral sclerosis disease based on convolutional neural network and reinforcement sample learning algorithm.

    Science.gov (United States)

    Sengur, Abdulkadir; Akbulut, Yaman; Guo, Yanhui; Bajaj, Varun

    2017-12-01

    Electromyogram (EMG) signals contain useful information of the neuromuscular diseases like amyotrophic lateral sclerosis (ALS). ALS is a well-known brain disease, which can progressively degenerate the motor neurons. In this paper, we propose a deep learning based method for efficient classification of ALS and normal EMG signals. Spectrogram, continuous wavelet transform (CWT), and smoothed pseudo Wigner-Ville distribution (SPWVD) have been employed for time-frequency (T-F) representation of EMG signals. A convolutional neural network is employed to classify these features. In it, Two convolution layers, two pooling layer, a fully connected layer and a lost function layer is considered in CNN architecture. The CNN architecture is trained with the reinforcement sample learning strategy. The efficiency of the proposed implementation is tested on publicly available EMG dataset. The dataset contains 89 ALS and 133 normal EMG signals with 24 kHz sampling frequency. Experimental results show 96.80% accuracy. The obtained results are also compared with other methods, which show the superiority of the proposed method.

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

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    Asako Otomo

    2012-01-01

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

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

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    Isabela M. Aparicio-Erriu

    2012-11-01

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

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

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    Ruben Gustav Leonhardt Real

    2014-07-01

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

  10. Exploring sarcasm detection in amyotrophic lateral sclerosis using ecologically valid measures

    Science.gov (United States)

    Staios, Mathew; Fisher, Fiona; Lindell, Annukka K.; Ong, Ben; Howe, Jim; Reardon, Katrina

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressive condition involving degeneration of both upper and lower motor neurons. Recent research suggests that a proportion of persons with ALS show a profile similar to that of frontotemporal dementia (FTD), with this group of ALS patients exhibiting social cognitive deficits. Although social cognitive deficits have been partially explored in ALS, research has yet to investigate such changes using ecologically valid measures. Therefore, this study aimed to further characterize the scope of social cognitive and emotion recognition deficits in non-demented ALS patients using an ecologically valid measure of social cognition. A sample of 35 ALS patients and 30 age-and-education matched controls were assessed using the Addenbrooke's Cognitive Examination, the Brixton Spatial Anticipation Test, and The Awareness of Social Inference Test, where participants were required to discriminate between various emotions and decipher socially challenging scenarios enacted in video vignettes. Participants with ALS showed significant difficulties in recognizing both sarcastic and paradoxical sarcastic statements, but not sincere statements, when compared to controls. After controlling for executive difficulties, ALS patients still displayed significant difficulties on tasks that assessed their comprehension of both sarcastic and paradoxical sarcastic statements. The inability to read social cues and make social inferences has the potential to place significant strain on familial/interpersonal relationships in ALS. The findings of this study highlight the importance of employing a broader range of neuropsychological assessment tools to aid in early detection of frontal lobe impairment in non-demented ALS patients. PMID:23734113

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

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    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.

  12. C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    He, Ji; Tang, Lu; Benyamin, Beben; Shah, Sonia; Hemani, Gib; Liu, Rong; Ye, Shan; Liu, Xiaolu; Ma, Yan; Zhang, Huagang; Cremin, Katie; Leo, Paul; Wray, Naomi R; Visscher, Peter M; Xu, Huji; Brown, Matthew A; Bartlett, Perry F; Mangelsdorf, Marie; Fan, Dongsheng

    2015-09-01

    A hexanucleotide repeat expansion (HRE) in the C9orf72 gene has been identified as the most common mutation in amyotrophic lateral sclerosis (ALS) among Caucasian populations. We sought to comprehensively evaluate genetic and epigenetic variants of C9orf72 and the contribution of the HRE in Chinese ALS cases. We performed fragment-length and repeat-primed polymerase chain reaction to determine GGGGCC copy number and expansion within the C9orf72 gene in 1092 sporadic ALS (sALS) and 1062 controls from China. We performed haplotype analysis of 23 single-nucleotide polymorphisms within and surrounding C9orf72. The C9orf72 HRE was found in 3 sALS patients (0.3%) but not in control subjects (p = 0.25). For 2 of the cases with the HRE, genotypes of 8 single-nucleotide polymorphisms flanking the HRE were inconsistent with the haplotype reported to be strongly associated with ALS in Caucasian populations. For these 2 individuals, we found hypermethylation of the CpG island upstream of the repeat, an observation not detected in other sALS patients (p HRE were highly associated with repeat lengths >8 repeats implying that both haplotypes may confer instability of repeat length. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. 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.

  14. Antioxidant capacity and protein oxidation in cerebrospinal fluid of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Siciliano, G; Piazza, S; Carlesi, C; Del Corona, A; Franzini, M; Pompella, A; Malvaldi, G; Mancuso, M; Paolicchi, A; Murri, L

    2007-05-01

    The causes of Amyotrophic Lateral Sclerosis (ALS) are unknown. A bulk of evidence supports the hypothesis that oxidative stress and mitochondrial dysfunction can be implicated in ALS pathogenesis. METHODS =: We assessed, in cerebrospinal fluid (CSF) and in plasma of 49 ALS patients and 8 controls, the amount of oxidized proteins (AOPP, advanced oxidation protein products), the total antioxidant capacity (FRA, the ferric reducing ability), and, in CSF, two oxidation products, the 4-hydroxynonenal and the sum of nitrites plus nitrates. The FRA was decreased (p = 0.003) in CSF, and AOPP were increased in both CSF (p = 0.0039) and plasma (p = 0.001) of ALS patients. The content of AOPP was differently represented in CSF of ALS clinical subsets, resulting in increase in the common and pseudopolyneuropathic forms (p < 0.001) and nearly undetectable in the bulbar form, as in controls. The sum of nitrites plus nitrates and 4-hydroxynonenal were unchanged in ALS patients compared with controls. Our results, while confirming the occurrence of oxidative stress in ALS, indicate how its effects can be stratified and therefore implicated differently in the pathogenesis of different clinical forms of ALS.

  15. Level of neurotoxic metals in amyotrophic lateral sclerosis: A population-based case-control study.

    Science.gov (United States)

    Bocca, Beatrice; Forte, Giovanni; Oggiano, Riccardo; Clemente, Simonetta; Asara, Yolande; Peruzzu, Angela; Farace, Cristiano; Pala, Salvatore; Fois, Alessandro Giuseppe; Pirina, Pietro; Madeddu, Roberto

    2015-12-15

    The association between exposure to toxic metals and amyotrophic lateral sclerosis (ALS) was explored in a population-based case-control study in the Sardinia island (Italy), a region characterized by elevated rates of ALS cases. In 34 patients with ALS (mean age, 62 ± 10 years) and 30 controls (mean age, 65 ± 11 years), Al, Cd, Hg, Mn and Pb were determined in blood, hair and urine by sector field inductively coupled mass spectrometry. Results indicated that, in blood, concentrations of Al (p=0.045) and Pb were higher (p=0.026) in ALS patients than in control subjects. In hair, a depletion of Al (p=0.006) and Mn (p=0.032) concentrations in ALS subjects respect to controls was found. In urine, no significant differences between cases and controls were observed. Thus, some metals seemed to be associated with ALS degeneration, but a definitive conclusion is still far considering the multiple risk factors (genetic mutations, environmental toxicants and stressors) involved in the disease. Finally, the interpretation that deregulated metal concentrations can be a consequence of the degenerative process, rather than a cause, is also valid. Copyright © 2015 Elsevier B.V. All rights reserved.

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

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    Kim Sung-chul

    2009-03-01

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

  17. Relationship between respiratory failure and plasma noradrenaline levels in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Yamashita, A; Koike, Y; Takahashi, A; Hirayama, M; Murakami, N; Sobue, G

    1997-08-01

    We evaluated plasma noradrenaline (NA) levels at test and during head-up tilt test in 20 patients with sporadic amyotrophic lateral sclerosis (ALS). Their fasting plasma NA levels ranged from 195 to 4227 pg/ml. The average plasma NA level was 483 pg/ml in five ambulatory patients, 341 in two wheelchair-bound patients, 1264 in 11 bedridden patients, and 208 in two respirator-dependent patients whose disability grading was the worst among the four groups. Arterial carbon dioxide (PCO2) was evaluated as a measure of respiratory function. The coefficient of correlation between PCO2 and plasma NA was r = 0.654 (p respiratory failure or lower motor neuron dysfunction may relate to the elevation of plasma NA levels. In the two bedridden patients, plasma NA levels and heart rate at rest increased significantly as the disease progressed. Cardiovascular responses to head-up tilting were normal. These data suggest that the elevation of plasma NA levels may be related to progression of respiratory failure and lower motor neuron dysfunction. In conclusion, sympathetic hyperactivity in ALS is considered to be not primary, but secondary to somatic motor disabilities and respiratory failure.

  18. 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.

  19. 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.

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

    Science.gov (United States)

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

    2013-01-01

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

  1. MRI Texture Analysis Reveals Deep Gray Nuclei Damage in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    de Albuquerque, Milena; Anjos, Lara G V; Maia Tavares de Andrade, Helen; de Oliveira, Márcia S; Castellano, Gabriela; Junqueira Ribeiro de Rezende, Thiago; Nucci, Anamarli; França Junior, Marcondes Cavalcante

    2016-01-01

    Amyotrophic Lateral Sclerosis (ALS) is characterized by extensive corticospinal damage, but extrapyramidal involvement is suggested in pathological studies. Texture analysis (TA) is an image processing technique that evaluates the distribution of gray levels between pixels in a given region of interest (ROI). It provides quantitative data and has been employed in several neurodegenerative disorders. Here, we used TA to investigate possible deep gray nuclei (DGN) abnormalities in a cohort of ALS patients. Thirty-two ALS patients and 32 healthy controls underwent MRI in a 3T scanner. The T1 volumetric sequence was used for DGN segmentation and extraction of 11 texture parameters using the MaZda software. Statistical analyses were performed using the Mann-Whitney non-parametric test, with a significance level set at α = 0.025 (FDR-corrected) for TA. Patients had significantly higher values for the parameter correlation (CO) in both thalami and in the right caudate nucleus compared to healthy controls. Also, the parameter Inverse Difference Moment or Homogeneity (IDM) presented significantly smaller values in the ALS group in both thalami. TA of T1 weighted images revealed DGN alterations in patients with ALS, namely in the thalami and caudate nuclei. Copyright © 2015 by the American Society of Neuroimaging.

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

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    Brian J. Wainger

    2014-04-01

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

  3. Magnetic resonance imaging and {sup 1}H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis

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    Sarchielli, P.; Gallai, V. [Neurological Clinic, Policlinico Monte Luce, Perugia (Italy); Pelliccioli, G.P.; Chiarini, P. [Dept. of Neuroradiology, Azienda Ospedaliera, Perugia (Italy); Tarducci, R.; Presciutti, O.; Gobbi, G. [Dept. of Medical Physics, Azienda Ospedaliera, Perugia (Italy)

    2001-03-01

    We aimed to increase confidence in the combined use of MRI and proton MR spectroscopy ({sup 1}H-MRS) in diagnosis of amyotrophic lateral sclerosis (ALS). We investigated 12 patients with ALS, seven definite and five probable, taking into account clinical measures of motor neuron function. On T2-weighted images we found high signal in the corticospinal tract in six and low signal in the primary motor cortex in seven of the 12 patients. Atrophy of the precentral gyrus was apparent in all the patients apart from one with probable ALS. Absolute quantification of cerebral metabolites using {sup 1}H-MRS demonstrated a significantly lower mean concentration of N-acetylaspartate (NAA) in the precentral gyrus of patients with probable and definite ALS (8.5 {+-} 0.62) than in control subjects (10.4 {+-} 0.71; P < 0.001). NAA concentration in primary motor cortex correlated with Norris scale scores (r = 0.30; P < 0.0001) but not with the ALS Functional Rating Scale score or disease duration. Significantly lower levels of NAA were detected in patients with low signal in the motor cortex than in those without (P < 0.01). Mean choline (Cho) and creatine (Cr) values did not differ between patients with ALS and controls. (orig.)

  4. Cerebrospinal fluid cytotoxicity does not affect survival in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Galán, L; Matías-Guiu, J; Matias-Guiu, J A; Yáñez, M; Pytel, V; Guerrero-Sola, A; Vela-Souto, A; Arranz-Tagarro, J A; Gómez-Pinedo, U; García, A G

    2017-09-01

    Cerebrospinal fluid (CSF) from some patients with amyotrophic lateral sclerosis (ALS) has been demonstrated to significantly reduce the neuronal viability of primary cell cultures of motor neurons. We aimed to study the potential clinical consequences associated with the cytotoxicity of CSF in a cohort of patients with ALS. We collected CSF from thirty-one patients with ALS. We analysed cytotoxicity by incubating it into the primary cultures of motor cortex neurons. Neural viability was quantified after 24 hours using the colorimetric MTT reduction assay. All patients were followed up from the moment of diagnosis to death, and a complete evaluation during disease progression and survival was performed, including gastrostomy and respiratory assistance. Twenty-one patients (67.7%) presented a cytotoxic CSF. There were no significant differences between patients with and without cytotoxicity regarding mean time from symptom onset to the diagnosis, from the diagnosis to death, from the diagnosis to respiratory assistance with BIPAP, from diagnosis to gastrostomy and from the onset of symptoms to death. In Cox regression analysis, bulbar onset, but not cytotoxicity, gender or age at onset, was associated with a lower risk of survival. Cerebrospinal fluid cytotoxicity was not associated with differential survival rates. This suggests that the presence of cytotoxicity in CSF, measured through neuronal viability in primary cultures of motor cortex neurons, could reflect different mechanisms of the disease, but it does not predict disease outcome. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. MRI of paraventricular white matter lesions in amyotrophic lateral sclerosis. Analysis by diffusion-weighted images

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    Segawa, Fuminori; Kinoshita, Masao (Toho Univ., Tokyo (Japan). Ohashi Hospital); Kishibayashi, Jun; Kamada, Kazuhiko; Sunohara, Nobuhiko

    1994-09-01

    Magnetic resonance images in some cases of amyotrophic lateral sclerosis (ALS) revealed abnormal signals in both the paraventriculer white matter and in the posterior limbs of the internal capsule. We examined T[sub 2]- and diffusion-weighted MR images of these lesions in 18 cases of ALS. There were symmetrical high-signal areas in the posterior limbs of the internal capsule in all of the cases. The high-signal areas in the internal capsule corresponded to the pyramidal tracts in the anatomical atlas by Talairach. In 5 of the cases of ALS, T[sub 2]-weighted MR images showed discrete paraventricular white matter lesions as well. The mean age of the ALS patients with paraventricular white matter lesions was higher than that of the ALS patients without such lesions. Proton densities calculated from the conventional MR images were higher in both the capsular and paraventricular lesions. The diffusion coefficients perpendicular to the pyramidal tract in the internal capsular lesions were within the normal range, where as the diffusion coefficients in the paraventricular lesions were increased in all directions. Thus, diffusion anisotropy was lost in the paraventricular lesions. These findings are similar to those observed in the white matter lesions of cerebro-vascular origin. As a result, the pathology of the paraventricular lesions in ALS was confirmed to be different from that of the internal capsular lesions. (author).

  6. 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.

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

    International Nuclear Information System (INIS)

    Willekens, Stefanie M.A.; Weehaeghe, Donatienne van; Damme, Philip van; Laere, Koen van

    2017-01-01

    During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although ["1"8F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression. (orig.)

  8. 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.)

  9. 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.)

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-04-01

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

  11. 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.

  12. Clinical epidemiology of amyotrophic lateral sclerosis in Liguria, Italy: An update of LIGALS register.

    Science.gov (United States)

    Scialò, Carlo; Novi, Giovanni; Bandettini di Poggio, Monica; Canosa, Antonio; Sormani, Maria Pia; Mandich, Paola; Origone, Paola; Truffelli, Romina; Mancardi, Giovanni Luigi; Caponnetto, Claudia

    Our objectives were: (1) to assess amyotrophic lateral sclerosis (ALS) incidence and its trend over time in Liguria, an Italian north-western region, performing an analysis of data prospectively collected from 1 January 2009 to 31 December 2014; (2) to determine the mean and median survival in the 2009-2014 Ligurian ALS incident cases; and (3) to evaluate the presence of disease prognostic factors. The Liguria Register for ALS (LIGALS) is an ongoing, multicentre prospective register enrolling all ALS incident cases in Liguria. Cases were identified using several concurrent sources. ALS diagnosis was based on El Escorial revised criteria (EEC-R). Two hundred and ninety-eight patients were enrolled in this study. The mean annual crude incidence rate in the 2009-2014 period was 3.11/100,000 population (95% CI 2.77-3.49); the point prevalence at 31 December 2014 was 7.85/100,000 (95% CI 6.54-9.36) population. Survival analysis demonstrated a median survival from symptom onset of 37.0 months (95% CI 32.0-42.0). In conclusion, ALS crude incidence in Liguria is higher compared to other Italian regions. Clinical and epidemiological data are comparable with those of the Italian ALS population. Survival analysis showed that higher age at onset, bulbar onset, definite EEC-R diagnostic category and a shorter diagnostic delay are related with worse outcomes.

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

    Energy Technology Data Exchange (ETDEWEB)

    Terao, Shin-ichi; Sobue, Gen; Higashi, Naoki; Takahashi, Masahiko; Suga, Hidemichi; Mitsuma, Terunori [Aichi Medical Univ., Nagakute (Japan)

    1995-03-01

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

  14. 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.

  15. 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

  16. 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.

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

    Science.gov (United States)

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

    2016-04-01

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

  18. 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.

  19. Neuroimaging to Investigate Multisystem Involvement and Provide Biomarkers in Amyotrophic Lateral Sclerosis

    Science.gov (United States)

    Pradat, Pierre-François; El Mendili, Mohamed-Mounir

    2014-01-01

    Neuroimaging allows investigating the extent of neurological systems degeneration in amyotrophic lateral sclerosis (ALS). Advanced MRI methods can detect changes related to the degeneration of upper motor neurons but have also demonstrated the participation of other systems such as the sensory system or basal ganglia, demonstrating in vivo that ALS is a multisystem disorder. Structural and functional imaging also allows studying dysfunction of brain areas associated with cognitive signs. From a biomarker perspective, numerous studies using diffusion tensor imaging showed a decrease of fractional anisotropy in the intracranial portion of the corticospinal tract but its diagnostic value at the individual level remains limited. A multiparametric approach will be required to use MRI in the diagnostic workup of ALS. A promising avenue is the new methodological developments of spinal cord imaging that has the advantage to investigate the two motor system components that are involved in ALS, that is, the lower and upper motor neuron. For all neuroimaging modalities, due to the intrinsic heterogeneity of ALS, larger pooled banks of images with standardized image acquisition and analysis procedures are needed. In this paper, we will review the main findings obtained with MRI, PET, SPECT, and nuclear magnetic resonance spectroscopy in ALS. PMID:24949452

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

    International Nuclear Information System (INIS)

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

    1995-01-01

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

  1. Non-invasive ventilation in amyotrophic lateral sclerosis: a 10 year population based study.

    Science.gov (United States)

    Chiò, Adriano; Calvo, Andrea; Moglia, Cristina; Gamna, Federica; Mattei, Alessio; Mazzini, Letizia; Mora, Gabriele

    2012-04-01

    To evaluate the clinical characteristics and outcome of non-invasive ventilation (NIV) in an epidemiological based series of amyotrophic lateral sclerosis (ALS) patients. The study was performed using data from the Piemonte and Valle d'Aosta Register for ALS, a prospective epidemiological register enrolling all ALS incident cases in two Italian regions. Among the 1260 patients incident in the period 1995-2004, 259 (20.6%) underwent NIV. Young male patients and subjects attending the tertiary ALS centres were more likely to undergo NIV. There was a progressive significant increase in the use of NIV during the study but was limited to patients attending the ALS tertiary centres. Median survival after NIV was 289 days (95% CI 255 to 333). In an epidemiological setting, NIV represents an increasingly utilised option for the treatment of respiratory disturbances in ALS and has favourable effects on survival, in particular among patients followed by tertiary ALS centres. Sociocultural factors, such as age, gender and marital status, strongly influence the probability of undergoing NIV. Efforts should be made to remove these obstacles in order to spread the use of NIV in all ALS patients with respiratory failure.

  2. Cortical drive to breathe in amyotrophic lateral sclerosis: a dyspnoea-worsening defence?

    Science.gov (United States)

    Georges, Marjolaine; Morawiec, Elise; Raux, Mathieu; Gonzalez-Bermejo, Jésus; Pradat, Pierre-François; Similowski, Thomas; Morélot-Panzini, Capucine

    2016-06-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing diaphragm weakness that can be partially compensated by inspiratory neck muscle recruitment. This disappears during sleep, which is compatible with a cortical contribution to the drive to breathe. We hypothesised that ALS patients with respiratory failure exhibit respiratory-related cortical activity, relieved by noninvasive ventilation (NIV) and related to dyspnoea.We studied 14 ALS patients with respiratory failure. Electroencephalographic recordings (EEGs) and electromyographic recordings of inspiratory neck muscles were performed during spontaneous breathing and NIV. Dyspnoea was evaluated using the Multidimensional Dyspnea Profile.Eight patients exhibited slow EEG negativities preceding inspiration (pre-inspiratory potentials) during spontaneous breathing. Pre-inspiratory potentials were attenuated during NIV (p=0.04). Patients without pre-inspiratory potentials presented more advanced forms of ALS and more severe respiratory impairment, but less severe dyspnoea. Patients with pre-inspiratory potentials had stronger inspiratory neck muscle activation and more severe dyspnoea during spontaneous breathing.ALS-related diaphragm weakness can engage cortical resources to augment the neural drive to breathe. This might reflect a compensatory mechanism, with the intensity of dyspnoea a negative consequence. Disease progression and the corresponding neural loss could abolish this phenomenon. A putative cognitive cost should be investigated. Copyright ©ERS 2016.

  3. Targeted assessment of lower motor neuron burden is associated with survival in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Devine, Matthew S; Ballard, Emma; O'Rourke, Peter; Kiernan, Matthew C; Mccombe, Pamela A; Henderson, Robert D

    2016-01-01

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

  4. Predictors of noninvasive ventilation tolerance in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Gruis, K L; Brown, D L; Schoennemann, A; Zebarah, V A; Feldman, E L

    2005-12-01

    Noninvasive ventilation (NIV) appears to improve survival and quality of life in patients with amyotrophic lateral sclerosis (ALS), but little is known about predictors of NIV tolerance. NIV use was assessed and clinical predictors of tolerance were investigated, using predictive modeling, in ALS patients diagnosed and followed in our clinic until death over a 4-year time period. Patients were prescribed NIV based on current practice parameters when respiratory symptoms were present or forced vital capacity was less than 50%. We prescribed NIV in 52% (72) of patients. For those prescribed NIV, information regarding tolerance was available for 50 patients, with 72% (36) tolerant to its use. Tolerance was six times more likely in limb-onset than bulbar-onset ALS patients, with a trend toward reduced tolerance in those with lower forced vital capacity at NIV initiation. Age, gender, and duration of disease were not predictors of NIV tolerance. We conclude that a majority of ALS patients who are prescribed NIV can successfully become tolerant to its use.

  5. Quality of life and psychosocial issues in ventilated patients with amyotrophic lateral sclerosis and their caregivers.

    Science.gov (United States)

    Kaub-Wittemer, Dagmar; Steinbüchel, Nicole von; Wasner, Maria; Laier-Groeneveld, Gerhard; Borasio, Gian Domenico

    2003-10-01

    Non-invasive ventilation (NIV) is an efficient palliative measure for symptoms of chronic hypoventilation in patients with amyotrophic lateral sclerosis (ALS), and can also lengthen survival. A subset of ALS patients undergoes tracheostomy ventilation (TV) for life prolongation. We investigated the quality of life (QOL) and psychosocial situation of 52 home ventilated ALS patients and their caregivers. The battery included sociodemographic, generic, and disease-specific variables, as well as the Profile of Mood States and the Munich Quality of Life Dimensions List. Data were compared between the NIV (n=32) and the TV (n=21) groups. Mean ventilation time was 14 months for NIV and 35 months for TV. Eighty-one percent of TV patients had been tracheotomized without informed consent. The data show a good overall QOL for both NIV and TV patients, but a very high burden of care for TV caregivers, 30% of whom rated their own QOL lower than their patient's QOL. Sexuality was an important issue. Thus, any assessment of QOL in a home palliative care situation should include the primary caregivers.

  6. [Management and treatment of respiratory failure associated with amyotrophic lateral sclerosis].

    Science.gov (United States)

    Danel-Brunaud, V; Perez, T; Just, N; Destée, A

    2005-04-01

    In amyotrophic lateral sclerosis (ALS), respiratory muscle involvement is highly predictive of survival and quality of life (QOL). There is compelling evidence that non invasive ventilation (NIV) prolongs survival by several months and improves QOL more than any other currently available treatment. Frequent testing of pulmonary function and regular evaluations are recommended since 1999 by the American Academy of Neurology in order to take appropriate treatment decisions. There are numerous tests available to evaluate respiratory status in ALS and it is important to know their sensitivity and specificity to recognize clinical risk situations. Some recent data suggest that sniff nasal pressure and maximal inspiratory pressure (MIP) can be performed reliably by most ALS patients and are more sensitive to decrements in inspiratory muscle strength than spirometry or arterial blood gasometry. Airway obstruction caused by ineffective coughing is the principal cause of intolerance to NIV. Several factors other than respiratory muscle strength may affect pulmonary function: postural changes, nutritional status, infectious disease, drugs. The neurologist has to coordinate multidisciplinary care, with attention to individual patient preferences, and with a frank and compassionate discussion between the patient, the family, the physicians and the caregivers.

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

    Science.gov (United States)

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

    2016-12-01

    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. Arterial blood gasses were assessed next to QOL by generic as well as disease-specific questionnaires. 77 patients started NIV: 30 with ALS and 47 without. Both groups showed significant improvements in blood gasses after 2 and 6 months. Compared to the non-ALS group, the ALS group had significantly worse scores after 6 months in MRF-28, SRI, HADS and SF-36 than the non-ALS group. This study shows that NIV improves gas exchange, both in patients with and without ALS. QOL improves markedly more in patients without ALS than in those with ALS, in whom only some domains improve. Our observation of little or no effect in ALS patients warrants a large study limited to ALS patients only.

  8. Relieving dyspnoea by non-invasive ventilation decreases pain thresholds in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Dangers, Laurence; Laviolette, Louis; Georges, Marjolaine; Gonzalez-Bermejo, Jésus; Rivals, Isabelle; Similowski, Thomas; Morelot-Panzini, Capucine

    2017-03-01

    Dyspnoea is a threatening sensation of respiratory discomfort that presents many similarities with pain. Experimental dyspnoea in healthy subjects induces analgesia. This 'dyspnoea-pain counter-irritation' could, in reverse, imply that relieving dyspnoea in patients with chronic respiratory diseases would lower their pain thresholds. We first determined pressure pain thresholds in 25 healthy volunteers (22-31 years; 13 men; handheld algometer), during unloaded breathing (BASELINE) and during inspiratory threshold loading (ITL). Two levels of loading were used, adjusted to induce dyspnoea self-rated at 60% or 80% of a 10 cm visual analogue scale (ITL6 and ITL8). 18 patients with chronic respiratory failure due to amyotrophic lateral sclerosis (ALS) were then studied during unassisted breathing and after 30 and 60 min of non-invasive ventilation-NIV30 and NIV60-(same dyspnoea evaluation). In healthy volunteers, pressure pain thresholds increased significantly in the deltoid during ITL6 (pNIV30 and NIV60 (pNIV in patients with ALS having respiratory failure is associated with decreased pressure pain thresholds. Clinical implications have yet to be determined, but this observation suggests that patients with ALS could become more susceptible to pain after the institution of NIV, hence the need for reinforced attention towards potentially painful diagnostic and therapeutic interventions. 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/.

  9. 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.

  10. Accepting or declining non-invasive ventilation or gastrostomy in amyotrophic lateral sclerosis: patients' perspectives.

    Science.gov (United States)

    Greenaway, L P; Martin, N H; Lawrence, V; Janssen, A; Al-Chalabi, A; Leigh, P N; Goldstein, L H

    2015-01-01

    The objective was to identify factors associated with decisions made by patients with amyotrophic lateral sclerosis (ALS) to accept or decline non-invasive ventilation (NIV) and/or gastrostomy in a prospective population-based study. Twenty-one people with ALS, recruited from the South-East ALS Register who made an intervention decision during the study timeframe underwent a face-to-face in-depth interview, with or without their informal caregiver present. Sixteen had accepted an intervention (11 accepted gastrostomy, four accepted NIV and one accepted both interventions). Five patients had declined gastrostomy. Thematic analysis revealed three main themes: (1) patient-centric factors (including perceptions of control, acceptance and need, and aspects of fear); (2) external factors (including roles played by healthcare professionals, family, and information provision); and (3) the concept of time (including living in the moment and the notion of 'right thing, right time'). Many aspects of these factors were inter-related. Decision-making processes for the patients were found to be complex and multifaceted and reinforce arguments for individualised (rather than 'algorithm-based') approaches to facilitating decision-making by people with ALS who require palliative interventions.

  11. Factors predicting survival in amyotrophic lateral sclerosis patients on non-invasive ventilation.

    Science.gov (United States)

    Gonzalez Calzada, Nuria; Prats Soro, Enric; Mateu Gomez, Lluis; Giro Bulta, Esther; Cordoba Izquierdo, Ana; Povedano Panades, Monica; Dorca Sargatal, Jordi; Farrero Muñoz, Eva

    2016-01-01

    Non invasive ventilation (NIV) improves quality of life and extends survival in amyotrophic lateral sclerosis (ALS) patients. However, few data exist about the factors related to survival. We intended to assess the predictive factors that influence survival in patients after NIV initiation. Patients who started NIV from 2000 to 2014 and were tolerant (compliance ≥ 4 hours) were included; demographic, disease related and respiratory variables at NIV initiation were analysed. Statistical analysis was performed using the Kaplan-Meier test and Cox proportional hazard models. 213 patients were included with median survival from NIV initiation of 13.5 months. In univariate analysis, the identified risk factors for mortality were severity of bulbar involvement (HR 2), Forced Vital Capacity (FVC) % (HR 0.99) and ALSFRS-R (HR 0.97). Multivariate analysis showed that bulbar involvement (HR 1.92) and ALSFRS-R (HR 0.97) were independent predictive factors of survival in patients on NIV. In our study, the two prognostic factors in ALS patients following NIV were the severity of bulbar involvement and ALSFRS-R at the time on NIV initiation. A better assessment of bulbar involvement, including evaluation of the upper airway, and a careful titration on NIV are necessary to optimize treatment efficacy.

  12. Bulbar impairment score and survival of stable amyotrophic lateral sclerosis patients after noninvasive ventilation initiation.

    Science.gov (United States)

    Sancho, Jesús; Martínez, Daniel; Bures, Enric; Díaz, José Luis; Ponz, Alejandro; Servera, Emilio

    2018-04-01

    There is general agreement that noninvasive ventilation (NIV) prolongs survival in amyotrophic lateral sclerosis (ALS) and that the main cause of NIV failure is the severity of bulbar dysfunction. However, there is no evidence that bulbar impairment is a contraindication for NIV. The aim of this study was to determine the effect of bulbar impairment on survival in ALS patients with NIV. ALS patients for whom NIV was indicated were included. Those patients who refused NIV were taken as the control group. 120 patients who underwent NIV and 20 who refused NIV were included. The NIV group presented longer survival (median 18.50 months, 95% CI 12.62-24.38 months) than the no-NIV group (3.00 months, 95% CI 0.82-5.18 months) (pNIV, adjusted for NIV failure, were severity of bulbar dysfunction (hazard ratio (HR) 0.5, 95% CI 0.92-0.97; p=0.001) and time spent with oxygen saturation measured by pulse oximetry NIV (HR 1.12, 95% CI 1.01-1.24; p=0.02). Severe bulbar impairment in ALS does not always prevent NIV from being used, but the severity of bulbar dysfunction at NIV initiation and %sleep S pO 2 NIV appear to be the main prognostic factors of NIV failure in ALS.

  13. Do patients with amyotrophic lateral sclerosis (ALS) have increased energy needs?

    Science.gov (United States)

    Vaisman, Nachum; Lusaus, Michal; Nefussy, Beatrice; Niv, Eva; Comaneshter, Doron; Hallack, Ron; Drory, Vivian E

    2009-04-15

    Nutritional status is a prognostic factor for survival in amyotrophic lateral sclerosis (ALS) patients. We investigated the contribution of some of the components contributing to resting energy expenditure (REE) in order to determine whether potentially higher energy needs should be considered for these patients. Thirty three ALS patients and 33 age- and gender-matched healthy controls participated. REE was measured by an open-circuit indirect calorimeter, body composition by dual energy X-ray absorptiometry, and estimated caloric intake by 7-day food records. Patients had lower body mass indices and lower lean body mass (LBM) than healthy controls. REE values (as a percentage of predicted) was similar but increased when normalized by LBM (Plater. A model for predicting measured REE was constructed based on the different components, with 86% prediction of its variability. ALS is associated with increased REE. Various factors, such as poor caloric intake and mechanical ventilation, may mask this tendency. All the above parameters need to be considered during nutritional intervention to prevent additional muscle loss.

  14. Long-Term Outcome of Amyotrophic Lateral Sclerosis in Korean Subjects.

    Science.gov (United States)

    Suh, Mi Ri; Choi, Won Ah; Choi, Young-Chul; Lee, Jang Woo; Hong, Jung Hwa; Park, Jihyun; Kang, Seong-Woong

    2017-12-01

    To report the latest long-term outcome of amyotrophic lateral sclerosis (ALS) and to analyze the predictors of prognosis. Subjects who were diagnosed with ALS between January 2005 and December 2009 at a single institute were followed up until death or up to December 2014. Data regarding age, sex, date of onset, date of diagnosis, presence of bulbar symptoms on onset, date of initiation of non-invasive ventilation (NIV), and the date of tracheostomy were collected. Survival was assessed using Kaplan-Meier curves and multivariate analyses of the risk of death were performed using the Cox proportional hazards model. Among 212 suspicious subjects, definite ALS was diagnosed in 182 subjects. The survival rate at 3 and 5 years from onset was 61.5% and 40.1%, respectively, and the survival rate at 3 and 5 years post-diagnosis was 49.5% and 24.2%, respectively. Further, 134 patients (134/182, 73.6%) were initiated on NIV, and among them, 90 patients (90/182, 49.5%) underwent tracheostomy. Male gender and onset age of ≥65 years were independent predictors of adverse survival. The analysis of long term survival in ALS showed excellent outcomes considering the overall poor prognosis of this disease.

  15. Decision Making About Gastrostomy and Noninvasive Ventilation in Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Martin, Naomi H; Lawrence, Vanessa; Murray, Joanna; Janssen, Anna; Higginson, Irene; Lyall, Rebecca; Burman, Rachel; Leigh, P Nigel; Al-Chalabi, Ammar; Goldstein, Laura H

    2016-08-01

    We used thematic analysis to investigate factors affecting decision making about gastrostomy and noninvasive ventilation (NIV) by people with Amyotrophic Lateral Sclerosis (ALS) from the viewpoint of the health care professionals (HCPs) supporting them. We conducted 20 in-depth interviews with 19 HCPs nominated by people with ALS who had made a decision to accept or decline NIV or gastrostomy. We found the main themes influencing decision making were patient-centric, caregiver-related or related to HCPs' own beliefs, perspectives, and actions. HCPs felt patients should be, and were, in control of decision making, although caregivers and HCPs played a role. The patient's evaluation of quality of life, the desirability of prolonging life, and acceptance of the disease and its progression by both patient and caregiver were the most important factors identified by HCPs. HCPs should be aware of the importance of multiprofessional discussions, and the potential influences (identified above) that might require discussion with patients and caregivers. © The Author(s) 2015.

  16. Diaphragm pacing and noninvasive respiratory management of amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Mahajan, Kedar R; Bach, John Robert; Saporito, Lou; Perez, Nick

    2012-12-01

    Although it is known that continuous noninvasive ventilation (CNIV) can prolong life in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), in this study we explore similar claims for diaphragm pacing (DP). NIV and DP users' vital capacities (VCs) over time and duration of NIV and CNIV dependence were analyzed for 354 non-DP and 8 DP ALS/MND patients. Patients had a higher rate of monthly VC decline before NIV use (5.1 ± 7.6%) than during NIV use (2.5 ± 3.6%) (P NIV for 19.9 ± 27.6 months until tracheostomy/death, whereas 113 others used it for 10.9 ± 10.5 months until CNIV dependence for another 12.8 ± 16.2 months. After placement, 7 DP users were CNIV dependent in 8.0 ± 7.0 months, whereas 6 underwent tracheostomy/died in 18.2 ± 13.7 months. CNIV prolonged the survival of 113 of the 354 non-DP and 6 DP ALS/MND patients by 12.8 and 10.2 months, respectively. DP provided no benefit on VC or mechanical ventilation-free survival. Copyright © 2012 Wiley Periodicals, Inc.

  17. Tolerance of Volume Control Noninvasive Ventilation in Subjects With Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Martínez, Daniel; Sancho, Jesús; Servera, Emilio; Marín, Julio

    2015-12-01

    Noninvasive ventilation (NIV) tolerance has been identified as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). Volume control continuous mandatory ventilation (VC-CMV) NIV has been associated with poor tolerance. The aim of this study was to determine the tolerance of subjects with ALS to VC-CMV NIV. This was a prospective study involving subjects with ALS who were treated with VC-CMV NIV. Respiratory and functional parameters were recorded when the subjects began ventilatory support. NIV tolerance was evaluated after 3 months. Eighty-seven subjects with ALS were included. After 3 months, 80 subjects (92%) remained tolerant of NIV. Tolerant subjects presented greater survival (median 22.0 months, 95% CI 14.78-29.21) than intolerant subjects (median 6.0 months, 95% CI 0.86-11.13) (P = .03). The variables that best predicted NIV tolerance were mechanically assisted cough peak flow (P = .01) and percentage of time spent with SpO2 NIV (P = .03) CONCLUSIONS: VC-CMV NIV provides high rates of NIV tolerance in subjects with ALS. Mechanically assisted cough peak flow and percentage of time spent with SpO2 NIV are the 2 factors associated with tolerance of VC-CMV NIV in subjects with ALS. Copyright © 2015 by Daedalus Enterprises.

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

    Science.gov (United States)

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

    2015-03-01

    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 secretion clearance. Non-invasive ventilation (NIV) is the first choice in treating respiratory insufficiency in ALS as it improves sleep-related symptoms, quality of life and life expectancy. Nevertheless, NIV is not always effective, probably due to bulbar dysfunction or anatomical abnormalities. As a result, tracheostomy ventilation (TV) may become necessary. In this case report, we present a 60-year-old female with ALS, for whom it was not possible to provide a sufficient tidal volume with NIV. A chin lift was performed while the patient was awake to see if a more anterior jaw position would lead to an increased tidal volume. As this was the case, a mandibular advancement device (MAD) was fabricated. With a combination of a MAD and NIV, the upper airway obstructions were overcome and a good ventilation and adherence to therapy were seen. When there is the presumption of airway obstructions in combination with an ineffective NIV, we advise to perform a chin lift to assess whether the obstructions can be overcome by a more anterior jaw position. If that is the case, NIV may be combined with MAD to establish effective ventilation and avoid the use of TV.

  19. MRI of paraventricular white matter lesions in amyotrophic lateral sclerosis. Analysis by diffusion-weighted images

    International Nuclear Information System (INIS)

    Segawa, Fuminori; Kinoshita, Masao; Kishibayashi, Jun; Kamada, Kazuhiko; Sunohara, Nobuhiko.

    1994-01-01

    Magnetic resonance images in some cases of amyotrophic lateral sclerosis (ALS) revealed abnormal signals in both the paraventriculer white matter and in the posterior limbs of the internal capsule. We examined T 2 - and diffusion-weighted MR images of these lesions in 18 cases of ALS. There were symmetrical high-signal areas in the posterior limbs of the internal capsule in all of the cases. The high-signal areas in the internal capsule corresponded to the pyramidal tracts in the anatomical atlas by Talairach. In 5 of the cases of ALS, T 2 -weighted MR images showed discrete paraventricular white matter lesions as well. The mean age of the ALS patients with paraventricular white matter lesions was higher than that of the ALS patients without such lesions. Proton densities calculated from the conventional MR images were higher in both the capsular and paraventricular lesions. The diffusion coefficients perpendicular to the pyramidal tract in the internal capsular lesions were within the normal range, where as the diffusion coefficients in the paraventricular lesions were increased in all directions. Thus, diffusion anisotropy was lost in the paraventricular lesions. These findings are similar to those observed in the white matter lesions of cerebro-vascular origin. As a result, the pathology of the paraventricular lesions in ALS was confirmed to be different from that of the internal capsular lesions. (author)

  20. Extent of cortical involvement in amyotrophic lateral sclerosis--an analysis based on cortical thickness.

    Science.gov (United States)

    Thorns, Johannes; Jansma, Henk; Peschel, Thomas; Grosskreutz, Julian; Mohammadi, Bahram; Dengler, Reinhard; Münte, Thomas F

    2013-10-18

    Besides the defining involvement of upper and lower motor neurons, the involvement of extramotor structures has been increasingly acknowledged in amyotrophic lateral sclerosis (ALS). Here we investigated a group of 14 mildly to moderately affected ALS patients and 14 age-matched healthy control participants using cortical thickness analysis. Cortical thickness was determined from high resolution 3D T1 magnetic resonance images and involved semiautomatic segmentation in grey and white matter, cortical alignment and determination of thickness using the Laplace method. In addition to a whole-cortex analysis a region of interest approach was applied. ALS patients showed regions of significant cortical thinning in the pre- and postcentral gyri bilaterally. Further regions of cortical thinning included superior and inferior parietal lobule, angular and supramarginal gyrus, insula, superior frontal, temporal and occipital regions, thus further substantiating extramotor involvement in ALS. A relationship between cortical thickness of the right superior frontal cortex and clinical severity (assessed by the ALS functional rating scale) was also demonstrated. Cortical thickness is reduced in ALS not only in motor areas but in widespread non-motor cortical areas. Cortical thickness is related to clinical severity.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2017-03-15

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

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

    Science.gov (United States)

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

    2015-11-01

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

  3. 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.

  4. 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.

  5. Epidemiology of Amyotrophic Lateral Sclerosis: A Population-Based Study in Israel.

    Science.gov (United States)

    Weil, Clara; Zach, Neta; Rishoni, Shay; Shalev, Varda; Chodick, Gabriel

    2016-01-01

    Globally, the annual incidence and prevalence of amyotrophic lateral sclerosis (ALS) are estimated at 1.9 and 4.5 per 100,000 population, respectively. This study is aimed at describing the epidemiology of ALS in Israel in a real-world setting. A retrospective study was performed using the databases of Maccabi Healthcare Services (MHS), a 2-million-member health maintenance organization in Israel. The study included all MHS adults diagnosed with ALS between 1997 and 2013. In 2013, characteristics of ALS patients were compared to those of age-sex-matched patients without ALS. Survival after ALS diagnosis was assessed until death and until tracheostomy or death (follow-up through 2014). In 2013 (n = 158), the prevalence of ALS was 8.1 per 100,000 population in MHS. In 1997-2013, a total of 375 ALS patients were diagnosed, corresponding to an average annual incidence of 1.8 per 100,000 population in MHS. The median survival from diagnosis to death was 3.5 years (95% CI 2.9-4.1), with approximately 28% surviving at least 10 years. Median tracheostomy-free survival was 2.5 years (95% CI 2.1-2.9). Results suggest that there is a relatively high prevalence of ALS in Israel. Further research is needed to investigate factors that may contribute to the survival of patients with ALS in Israel. © 2016 S. Karger AG, Basel.

  6. 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.

  7. 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

  8. Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model.

    Science.gov (United States)

    Lee, Joo-Yong; Kawaguchi, Yoshiharu; Li, Ming; Kapur, Meghan; Choi, Su Jin; Kim, Hak-June; Park, Song-Yi; Zhu, Haining; Yao, Tso-Pang

    2015-01-01

    Aberrant accumulation of protein aggregates is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although a buildup of protein aggregates frequently leads to cell death, whether it is the key pathogenic factor in driving neurodegenerative disease remains controversial. HDAC6, a cytosolic ubiquitin-binding deacetylase, has emerged as an important regulator of ubiquitin-dependent quality control autophagy, a lysosome-dependent degradative system responsible for the disposal of misfolded protein aggregates and damaged organelles. Here, we show that in cell models HDAC6 plays a protective role against multiple disease-associated and aggregation-prone cytosolic proteins by facilitating their degradation. We further show that HDAC6 is required for efficient localization of lysosomes to protein aggregates, indicating that lysosome targeting to autophagic substrates is regulated. Supporting a critical role of HDAC6 in protein aggregate disposal in vivo, genetic ablation of HDAC6 in a transgenic SOD1G93A mouse, a model of ALS, leads to dramatic accumulation of ubiquitinated SOD1G93A protein aggregates. Surprisingly, despite a robust buildup of SOD1G93A aggregates, deletion of HDAC6 only moderately modified the motor phenotypes. These findings indicate that SOD1G93A aggregation is not the only determining factor to drive neurodegeneration in ALS, and that HDAC6 likely modulates neurodegeneration through additional mechanisms beyond protein aggregate clearance. © 2015 S. Karger AG, Basel.

  9. Predictors of health-related quality of life in people with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Sandstedt, Petter; Johansson, Sverker; Ytterberg, Charlotte; Ingre, Caroline; Holmqvist, Lotta Widén; Kierkegaard, Marie

    2016-11-15

    Knowledge of factors influencing health-related quality of life (HRQL) in people with amyotrophic lateral sclerosis (ALS) is important because some factors might be amenable to intervention. The aim was to describe and explore the effects of disease severity, fatigue, anxiety, depression, frequency of social and lifestyle activities, coping capacity and mechanical ventilator use on HRQL in people with ALS. Sixty people with ALS were enrolled in this cross-sectional study. Data were collected with questionnaires during home visits. The Sickness Impact Profile and the EuroQol Visual Analogue Scale were used to assess HRQL. Multivariate regression analyses explored associations between HRQL and independent factors. Low frequency of social and lifestyle activities, and severe disease, were associated with worse HRQL, explaining 57% of total variance in the Sickness Impact Profile physical score. Severe disease, weak coping capacity and anxiety and/or depression were associated with worse HRQL, explaining 33% of total variance in Sickness Impact Profile psychosocial score. Fatigue and mechanical ventilator use were associated with worse HRQL, explaining 17% of variance in the EuroQol Visual Analogue Scale. Knowledge and understanding of how frequency of social and lifestyle activities, disease severity, coping capacity, anxiety and/or depression, fatigue and ventilator use contribute to and predict self-rated HRQL can optimize person-centred care and support. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Yoshiaki Furukawa

    2012-01-01

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

  11. Blood trace metals in a sporadic amyotrophic lateral sclerosis geographical cluster.

    Science.gov (United States)

    De Benedetti, Stefano; Lucchini, Giorgio; Del Bò, Cristian; Deon, Valeria; Marocchi, Alessandro; Penco, Silvana; Lunetta, Christian; Gianazza, Elisabetta; Bonomi, Francesco; Iametti, Stefania

    2017-06-01

    Amyotrophic lateral sclerosis (ALS) is a fatal disorder with unknown etiology, in which genetic and environmental factors interplay to determine the onset and the course of the disease. Exposure to toxic metals has been proposed to be involved in the etiology of the disease either through a direct damage or by promoting oxidative stress. In this study we evaluated the concentration of a panel of metals in serum and whole blood of a small group of sporadic patients, all living in a defined geographical area, for which acid mine drainage has been reported. ALS prevalence in this area is higher than in the rest of Italy. Results were analyzed with software based on artificial neural networks. High concentrations of metals (in particular Se, Mn and Al) were associated with the disease group. Arsenic serum concentration resulted lower in ALS patients, but it positively correlated with disease duration. Comet assay was performed to evaluate endogenous DNA damage that resulted not different between patients and controls. Up to now only few studies considered geographically well-defined clusters of ALS patients. Common geographical origin among patients and controls gave us the chance to perform metallomic investigations under comparable conditions of environmental exposure. Elaboration of these data with software based on machine learning processes has the potential to be extremely useful to gain a comprehensive view of the complex interactions eventually leading to disease, even in a small number of subjects.

  12. [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.

  13. Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans.

    Science.gov (United States)

    Mazzini, Letizia; Fagioli, Franca; Boccaletti, Riccardo; Mareschi, Katia; Oliveri, Giuseppe; Olivieri, Carlo; Pastore, Ilaria; Marasso, Roberto; Madon, Enrico

    2003-09-01

    Recently it has been shown in animal models of amyotrophic lateral sclerosis (ALS) that stem cells significantly slow the progression of the disease and prolong survival. We have evaluated the feasibility and safety of a method of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well-monitored patients with ALS. Bone marrow collection was performed according to the standard procedure by aspiration from the posterior iliac crest. Ex vivo expansion of mesenchymal stem cells was induced according to Pittenger's protocol. The cells were suspended in 2 ml of autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector. No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation (4 patients) which was reversible after a mean period of three days after surgery, and leg sensory dysesthesia (5 patients) which was reversible after a mean period of six weeks after surgery. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. Our results appear to demonstrate that the procedures of ex vivo expansion of autologous mesenchymal stem cells and of transplantation into the spinal cord of humans are safe and well tolerated by ALS patients.

  14. 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.

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

    Science.gov (United States)

    Eidenberger, Margit; Nowotny, Silvia

    2014-01-01

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

  16. Stem cell transplantation for amyotrophic lateral sclerosis: therapeutic potential and perspectives on clinical translation.

    Science.gov (United States)

    Faravelli, Irene; Riboldi, Giulietta; Nizzardo, Monica; Simone, Chiara; Zanetta, Chiara; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

    2014-09-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by degeneration of upper and lower motor neurons. There are currently no clinically impactful treatments for this disorder. Death occurs 3-5 years after diagnosis, usually due to respiratory failure. ALS pathogenesis seems to involve several pathological mechanisms (i.e., oxidative stress, inflammation, and loss of the glial neurotrophic support, glutamate toxicity) with different contributions from environmental and genetic factors. This multifaceted combination highlights the concept that an effective therapeutic approach should counteract simultaneously different aspects: stem cell therapies are able to maintain or rescue motor neuron function and modulate toxicity in the central nervous system (CNS) at the same time, eventually representing the most comprehensive therapeutic approach for ALS. To achieve an effective cell-mediated therapy suitable for clinical applications, several issues must be addressed, including the identification of the most performing cell source, a feasible administration protocol, and the definition of therapeutic mechanisms. The method of cell delivery represents a major issue in developing cell-mediated approaches since the cells, to be effective, need to be spread across the CNS, targeting both lower and upper motor neurons. On the other hand, there is the need to define a strategy that could provide a whole distribution without being too invasive or burdened by side effects. Here, we review the recent advances regarding the therapeutic potential of stem cells for ALS with a focus on the minimally invasive strategies that could facilitate an extensive translation to their clinical application.

  17. Brain signature of mild stages of cognitive and behavioral impairment in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Branco, Lucas M T; de Rezende, Thiago J R; Roversi, Caroline de O; Zanao, Tamires; Casseb, Raphael F; de Campos, Brunno M; França, Marcondes C

    2018-02-28

    We aimed to assess the brain signature of cognitive and behavioral impairment in C9orf72-negative non-demented ALS patients. The study included 50 amyotrophic lateral sclerosis (ALS) patients (out of 75 initially recruited) and 38 healthy controls. High-resolution T1-weighted and spin-echo diffusion tensor images were acquired in a 3T MRI scanner. The multi atlas-based analysis protocol and the FreeSurfer tool were employed for gray matter assessment, and fiber tractography for white matter evaluation. Cognitively impaired ALS patients (n = 12) had bilateral amygdalae and left thalamic volumetric reduction compared to non-impaired ALS patients. Behaviorally impaired ALS patients (n = 14) had lower fractional anisotropy (FA) at the fornix in comparison with healthy subjects. These parameters did correlate with cognitive/behavioral scores, but not with motor-functional parameters in the ALS cohort. We believe that basal ganglia and fornix damage might be related to cognitive and behavioral impairment across ALS-frontotemporal dementia continuum. Also, distinct anatomical areas seem to influence the behavioral and cognitive status of these individuals. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Amyotrophic lateral sclerosis-like presentation in a HIV-positive patient.

    Science.gov (United States)

    Anand, Kuljeet Singh; Wadhwa, Ankur; Garg, Jyoti; Mahajan, Rakesh Kumar

    2014-01-01

    There has been several reports of an MND like syndrome in HIV-1 infection, however the data is still sparse. Furthermore, HIV-associated amyotrophic lateral sclerosis (ALS) syndrome differs from the classical ALS in some key aspects.. A 44-year-old male presented with a history of insidious onset and gradually progressive asymmetric weakness of lower limbs. He also complained of thinning in both legs, the left leg more than the right since 1 year along with spontaneous twitching of muscles in both the thighs. On neurological examination, the assessment of higher mental functions was normal. There were no cranial nerve deficits. Motor power was grade 5/5 (Medical Research Council scale) in both the upper limbs and 4+ at hips and knees bilaterally, 5 at right ankle, and 4+ at left ankle. All the deep tendon reflexes were brisk with extensor planter responses. There were no cerebellar signs or sensory deficits. HIV-1 was reactive in enzyme-linked immunosorbent assay. Electrophysiological studies were conducted per the MND protocol.None of the nerves studied showed an abnormal drop in compound muscle action potential amplitude with proximal stimulation. There was evidence of diffuse spontaneous activity, which manifests as fibrillation and fasciculation potentials in most muscles tested . Overall there seems to be sufficient evidence to implicate HIV as a potential cause of an ALS-like disorder, but one must also consider the possibility of coincidental HIV infection in patients who have sporadic ALS. © The Author(s) 2014.

  19. Motoneuron survival is promoted by specific exercise in a mouse model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Deforges, Séverine; Branchu, Julien; Biondi, Olivier; Grondard, Clément; Pariset, Claude; Lécolle, Sylvie; Lopes, Philippe; Vidal, Pierre-Paul; Chanoine, Christophe; Charbonnier, Frédéric

    2009-07-15

    Several studies using transgenic mouse models of familial amyotrophic lateral sclerosis (ALS) have reported a life span increase in exercised animals, as long as animals are submitted to a moderate-intensity training protocol. However, the neuroprotective potential of exercise is still questionable. To gain further insight into the cellular basis of the exercise-induced effects in neuroprotection, we compared the efficiency of a swimming-based training, a high-frequency and -amplitude exercise that preferentially recruits the fast motor units, and of a moderate running-based training, that preferentially triggers the slow motor units, in an ALS mouse model. Surprisingly, we found that the swimming-induced benefits sustained the motor function and increased the ALS mouse life span by about 25 days. The magnitude of this beneficial effect is one of the highest among those induced by any therapeutic strategy in this disease. We have shown that, unlike running, swimming significantly delays spinal motoneuron death and, more specifically, the motoneurons of large soma area. Analysis of the muscular phenotype revealed a swimming-induced relative maintenance of the fast phenotype in fast-twitch muscles. Furthermore, the swimming programme preserved astrocyte and oligodendrocyte populations in ALS spinal cord. As a whole, these data are highly suggestive of a causal relationship not only linking motoneuron activation and protection, but also motoneuron protection and the maintenance of the motoneuron surrounding environment. Basically, exercise-induced neuroprotective mechanisms provide an example of the molecular adaptation of activated motoneurons.

  20. Radiation therapy for hypersalivation: a prospective study in 50 amyotrophic lateral sclerosis patients.

    Science.gov (United States)

    Assouline, Avi; Levy, Antonin; Abdelnour-Mallet, Maya; Gonzalez-Bermejo, Jesus; Lenglet, Timothée; Le Forestier, Nadine; Salachas, François; Bruneteau, Gaelle; Meininger, Vincent; Delanian, Sylvie; Pradat, Pierre-François

    2014-03-01

    This study aimed to evaluate the efficiency and the tolerance of radiation therapy (RT) on salivary glands in a large series of amyotrophic lateral sclerosis (ALS) patients with hypersalivation. Fifty ALS patients that had medically failure pretreatment were included in this prospective study. RT was delivered through a conventional linear accelerator with 6-MV photons and 2 opposed beams fields including both submandibular glands and two-thirds of both parotid glands. Total RT dose was 10 Gy in 2 fractions (n=30) or 20 Gy in 4 fractions (n=20). RT efficacy was assessed with the 9-grade Sialorrhea Scoring Scale (SSS), recently prospectively validated as the most effective and sensitive tool to measure sialorrhea in ALS patients. At the end of RT, all patients had improved: 46 had a complete response (92% CR, SSS 1-3) and 4 had a partial response (8% PR, SSS 4-5). A significant lasting salivary reduction was observed 6 months after RT completion: there was 71% CR and 26% PR, and there was a significant SSS reduction versus baseline (Pprotocol (P=.02), and 8 of 9 patients (89%) receiving a second RT course had previously been treated within the 10-Gy protocol. Radiation therapy of 20 Gy in 4 fractions is an efficient and safe treatment for ALS patients with sialorrhea. A shorter RT course (10 Gy in 2 fractions) may be proposed in patients in poor medical condition. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Efficacy of hypnosis-based treatment in amyotrophic lateral sclerosis: a pilot study.

    Science.gov (United States)

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

    2012-01-01

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

  2. Brain-computer interface (BCI) evaluation in people with amyotrophic lateral sclerosis.

    Science.gov (United States)

    McCane, Lynn M; Sellers, Eric W; McFarland, Dennis J; Mak, Joseph N; Carmack, C Steve; Zeitlin, Debra; Wolpaw, Jonathan R; Vaughan, Theresa M

    2014-06-01

    Brain-computer interfaces (BCIs) might restore communication to people severely disabled by amyotrophic lateral sclerosis (ALS) or other disorders. We sought to: 1) define a protocol for determining whether a person with ALS can use a visual P300-based BCI; 2) determine what proportion of this population can use the BCI; and 3) identify factors affecting BCI performance. Twenty-five individuals with ALS completed an evaluation protocol using a standard 6 × 6 matrix and parameters selected by stepwise linear discrimination. With an 8-channel EEG montage, the subjects fell into two groups in BCI accuracy (chance accuracy 3%). Seventeen averaged 92 (± 3)% (range 71-100%), which is adequate for communication (G70 group). Eight averaged 12 (± 6)% (range 0-36%), inadequate for communication (L40 subject group). Performance did not correlate with disability: 11/17 (65%) of G70 subjects were severely disabled (i.e. ALSFRS-R < 5). All L40 subjects had visual impairments (e.g. nystagmus, diplopia, ptosis). P300 was larger and more anterior in G70 subjects. A 16-channel montage did not significantly improve accuracy. In conclusion, most people severely disabled by ALS could use a visual P300-based BCI for communication. In those who could not, visual impairment was the principal obstacle. For these individuals, auditory P300-based BCIs might be effective.

  3. Validation of a new strength measurement device for amyotrophic lateral sclerosis clinical trials.

    Science.gov (United States)

    Andres, Patricia L; Skerry, Linda M; Munsat, Theodore L; Thornell, Brenda J; Szymonifka, Jackie; Schoenfeld, David A; Cudkowicz, Merit E

    2012-01-01

    Strength measures with reduced variability and higher sensitivity could improve efficiency in clinical trials of amyotrophic lateral sclerosis (ALS). The Accurate Test of Limb Isometric Strength (ATLIS) was developed to precisely and conveniently measure force in 12 muscle groups. In this study we evaluate the reliability and validity of the ATLIS testing protocol. Twenty healthy adults and 10 patients with ALS were tested twice by the same or by different evaluators to determine test-retest and interrater reliability. Twenty healthy adults were examined using ATLIS and a well-validated strength testing protocol (TQNE) to assess criterion-based validity. Mean absolute variation between tests was 8.6%, and intraclass correlation coefficients for each muscle group were high (range 0.82-0.99). The Pearson correlation coefficient of mean ATLIS and TQNE scores was 0.90. A subject survey demonstrated high user acceptance of ATLIS. ATLIS is convenient for patients and evaluators, produces precise strength measurements, and is easily moved between examining rooms. Copyright © 2011 Wiley Periodicals, Inc.

  4. 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.

  5. Proteome analysis of body fluids for amyotrophic lateral sclerosis biomarker discovery.

    Science.gov (United States)

    Krüger, Thomas; Lautenschläger, Janin; Grosskreutz, Julian; Rhode, Heidrun

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of motor neurons leading to death of the patients, mostly within 2-5 years after disease onset. The pathomechanism of motor neuron degeneration is only partially understood and therapeutic strategies based on mechanistic insights are largely ineffective. The discovery of reliable biomarkers of disease diagnosis and progression is the sine qua non of both the revelation of insights into the ALS pathomechanism and the assessment of treatment efficacies. Proteomic approaches are an important pillar in ALS biomarker discovery. Cerebrospinal fluid is the most promising body fluid for differential proteome analyses, followed by blood (serum, plasma), and even urine and saliva. The present study provides an overview about reported peptide/protein biomarker candidates that showed significantly altered levels in certain body fluids of ALS patients. These findings have to be discussed according to proposed pathomechanisms to identify modifiers of disease progression and to pave the way for the development of potential therapeutic strategies. Furthermore, limitations and advantages of proteomic approaches for ALS biomarker discovery in different body fluids and reliable validation of biomarker candidates have been addressed. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.

    Science.gov (United States)

    Deschauer, M; Gaul, C; Behrmann, C; Prokisch, H; Zierz, S; Haack, T B

    2012-11-01

    Mutations in C19orf12 have been recently identified as the molecular genetic cause of a subtype of neurodegeneration with brain iron accumulation (NBIA). Given the mitochondrial localization of the gene product the new NBIA subtype was designated mitochondrial membrane protein-associated neurodegeneration. Frequent features in the patients described so far included extrapyramidal signs and pyramidal tract involvement. Here, we report three C19orf12-mutant patients from two families presenting with predominant upper and lower motor neuron dysfunction mimicking amyotrophic lateral sclerosis with juvenile onset. While extrapyramidal signs were absent, all patients showed neuropsychological abnormalities with disinhibited or impulsive behavior. Optic atrophy was present in the simplex case. T2-weighted cranial MRI showed hypointensities suggestive of iron accumulation in the globi pallidi and the midbrain in all patients. Sequence analysis of C19orf12 revealed a novel mutation, p.Gly66del, compound heterozygous with known mutations in all patients. These patients highlight that C19orf12 defects should be considered as a differential diagnosis in patients with juvenile onset motor neuron diseases. Patients have to be examined carefully for neuropsychological abnormalities, optic neuropathy, and signs of brain iron accumulation in MRI.

  7. 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.

  8. 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.

  9. Parkinson's disease-like midbrain hyperechogenicity is frequent in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Fathinia, Panteha; Hermann, Andreas; Reuner, Ulrike; Kassubek, Jan; Storch, Alexander; Ludolph, Albert C

    2013-02-01

    Clinical and neuroimaging data suggest impairment of the nigrostriatal system in amyotrophic lateral sclerosis (ALS). We thus hypothesized whether Parkinson's disease (PD)-like midbrain sonography findings are also present in ALS. Eighty-six patients with the diagnosis of possible or definite ALS according to revised El Escorial criteria were examined by transcranial B-mode sonography compared to 76 age- and gender-matched controls and 33 PD patients. Hyperechogenic areas of the midbrain representing the substantia nigra were measured planimetrically using standard protocols. In subjects with sufficient temporal acoustic bone windows, mean midbrain hyperechogenic areas were significantly higher in ALS (0.251 ± 0.104 cm(2)) and PD patients (0.286 ± 0.078 cm(2)) compared to controls (0.091 ± 0.054 cm(2)) with no significant difference between ALS and PD patients (one-way ANOVA: F value = 94.3; P diagnosis and differential diagnosis of PD and ALS alike.

  10. Repetitive nerve stimulation as a diagnostic aid for distinguishing cervical spondylotic amyotrophy from amyotrophic lateral sclerosis.

    Science.gov (United States)

    Zheng, Chaojun; Jin, Xiang; Zhu, Yu; Lu, Feizhou; Jiang, Jianyuan; Xia, Xinlei

    2017-07-01

    To identify and compare the features of compound muscle action potential (CMAP) decrements in repetitive nerve stimulation (RNS) in patients with cervical spondylotic amyotrophy (CSA) and in patients with amyotrophic lateral sclerosis (ALS). The cohort consisted of 43 CSA (distal-type to proximal-type ratio: 27-16) and 35 ALS patients. Five muscles, including abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), middle deltoid (Del), and upper trapezius (Trap), were tested by 3-Hz RNS. Decrements greater than cutoff values (APB > 5.8%; ADM > 4.8%; BB > 5.2%; Del > 6%; Trap > 5.1%) determined using receiver operating characteristic (ROC) curves were defined as abnormal, and the conventional criterion (≥10%) was also considered. A significant CMAP decrement (>cutoff values) was recorded from at least one tested muscle in 91.4% of ALS patients, and was most common in the proximal muscle, a finding that differed significantly from CSA patients (32.6%, P  0.05). The application of RNS, especially in proximal muscles, may provide a simple accurate and noninvasive supplementary test for distinguishing CSA from ALS, even in the early stage of these diseases. A combination of RNS, needle EMG, clinical features and cervical magnetic resonance imaging may yield sufficient diagnostic information to differentiate CSA and ALS.

  11. Dysgraphia in Patients with Primary Lateral Sclerosis: A Speech-Based Rehearsal Deficit?

    Science.gov (United States)

    Zago, S.; Poletti, B.; Corbo, M.; Adobbati, L.; Silani, V.

    2008-01-01

    The present study aims to demonstrate that errors when writing are more common than expected in patients affected by primary lateral sclerosis (PLS) with severe dysarthria or complete mutism, independent of spasticity. Sixteen patients meeting Pringle’s et al. [34] criteria for PLS underwent standard neuropsychological tasks and evaluation of writing. We assessed writing abilities in spelling through dictation in which a set of words, non-words and short phrases were presented orally and by composing words using a set of preformed letters. Finally, a written copying task was performed with the same words. Relative to controls, PLS patients made a greater number of spelling errors in all writing conditions, but not in copy task. The error types included: omissions, transpositions, insertions and letter substitutions. These were equally distributed on the writing task and the composition of words with a set of preformed letters. This pattern of performance is consistent with a spelling impairment. The results are consistent with the concept that written production is critically dependent on the subvocal articulatory mechanism of rehearsal, perhaps at the level of retaining the sequence of graphemes in a graphemic buffer. In PLS patients a disturbance in rehearsal opportunity may affect the correct sequencing/assembly of an orthographic representation in the written process. PMID:19096141

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

    Science.gov (United States)

    2013-01-01

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

  13. 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.

  14. 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.

  15. Neuropsychological deficits in amyotrophic lateral sclerosis (ALS: a South India experience

    Directory of Open Access Journals (Sweden)

    Jamuna Rajeswaran

    2013-04-01

    Full Text Available ALS is a terminal progressive degenerative neurological disorder studies suggest that approximately 35% to 52% of ALS patients experience cognitive deficits which may be identified early in the course of the disease. Cognitive deficits being the integral part of the disease has not been studied in the Indian setting. This is one of the first studies assessing the pattern of cognitive impairment in ALS in the Indian condition. The objective is to examine the neuropsychological profile of amyotrophic lateral sclerosis. Cognitive function was studied in 20 ALS patients: mean age 45.85±13.9 years (22-65. Neuropsychological test battery was administered. In all 21 test were administered individually in 4-5 sessions which lasted for 7-8 hours. The results show that the majority of patients were from lower/middle socio-economic background. Scores were compared with gender, age and education specific norms, wherein scores falling below 15th percentile of the normative data were treated as deficits. ALS-associated cognitive impairments include deficiencies in visual attention, working memory, fluency, cognitive flexibility, response inhibition, planning, problem solving, and visual-perceptual skills.These impairments indicate executive dysfunction. In conclusion ALS is a disease that affects higher cognitive frontal functions, especially the EF.

  16. 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.

  17. Magnetic resonance imaging and 1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis

    International Nuclear Information System (INIS)

    Sarchielli, P.; Gallai, V.; Pelliccioli, G.P.; Chiarini, P.; Tarducci, R.; Presciutti, O.; Gobbi, G.

    2001-01-01

    We aimed to increase confidence in the combined use of MRI and proton MR spectroscopy ( 1 H-MRS) in diagnosis of amyotrophic lateral sclerosis (ALS). We investigated 12 patients with ALS, seven definite and five probable, taking into account clinical measures of motor neuron function. On T2-weighted images we found high signal in the corticospinal tract in six and low signal in the primary motor cortex in seven of the 12 patients. Atrophy of the precentral gyrus was apparent in all the patients apart from one with probable ALS. Absolute quantification of cerebral metabolites using 1 H-MRS demonstrated a significantly lower mean concentration of N-acetylaspartate (NAA) in the precentral gyrus of patients with probable and definite ALS (8.5 ± 0.62) than in control subjects (10.4 ± 0.71; P < 0.001). NAA concentration in primary motor cortex correlated with Norris scale scores (r = 0.30; P < 0.0001) but not with the ALS Functional Rating Scale score or disease duration. Significantly lower levels of NAA were detected in patients with low signal in the motor cortex than in those without (P < 0.01). Mean choline (Cho) and creatine (Cr) values did not differ between patients with ALS and controls. (orig.)

  18. Cognitive deficits in amyotrophic lateral sclerosis evaluated by event-related potentials.

    Science.gov (United States)

    Ogawa, Tomohiro; Tanaka, Hideaki; Hirata, Koichi

    2009-04-01

    To determine the cognitive profiles in non-demented, relatively less handicapped patients with early-stage sporadic amyotrophic lateral sclerosis (ALS) by using neuropsychological tests, event-related potentials (ERPs) and clinical scale. We recruited 19 patients with sporadic ALS (eight with limb-onset, 11 with bulbar-onset) and 19 controls. In addition to the mini-mental state examination and the Wechsler adult intelligence scale-revised, we assessed the frontal lobe function with Wisconsin card sorting test, Stroop test and trail making test. We used auditory 'oddball' counting paradigm for the ERPs under 20-channel electroencephalogram (EEG) recording. Global field power (GFP) was computed, and its peak amplitudes and latencies of N1/N2/P3 were determined. The results of ERP and neuropsychological tests were correlated with respiratory function and clinical scale. No global cognitive impairment except for subtle frontal dysfunction was detected, although N1/N2/P3 GFP latencies were significantly prolonged in ALS patients than in the controls. Vital capacity correlated with P3 GFP amplitude, and the relative bulbar functional rating scale correlated with P3 GFP latency. Our findings indicated the presence of sub-clinical cognitive deficits in non-demented, spora