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Primary lateral sclerosis

Brittany N Flores, Mark E Dulchavsky, Amy Krans, Michael R Sawaya, Henry L Paulson, Peter K Todd, Sami J Barmada, Magdalena I Ivanova
Hexanucleotide repeat expansions in C9orf72 are the most common inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansions elicit toxicity in part through repeat-associated non-AUG (RAN) translation of the intronic (GGGGCC)n sequence into dipeptide repeat-containing proteins (DPRs). Little is known, however, about the structural characteristics and aggregation propensities of the dipeptide units comprising DPRs. To address this question, we synthesized dipeptide units corresponding to the three sense-strand RAN translation products, analyzed their structures by circular dichroism, electron microscopy and dye binding assays, and assessed their relative toxicity when applied to primary cortical neurons...
2016: PloS One
Christopher P Webster, Emma F Smith, Andrew J Grierson, Kurt J De Vos
A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common genetic defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a resulting loss of C9orf72 protein function has been suggested as a possible pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum and hippocampus, indicating possible autophagy deficits in these patients...
October 21, 2016: Small GTPases
Heiko Braak, Albert C Ludolph, Manuela Neumann, John Ravits, Kelly Del Tredici
Two nerve cells types, Betz cells in layer Vb of the primary motor neocortex and α-motoneurons of the lower brainstem and spinal cord, become involved at the beginning of the pathological cascade underlying sporadic amyotrophic lateral sclerosis (sALS). In both neuronal types, the cell nuclei forfeit their normal (non-phosphorylated) expression of the 43-kDa transactive response DNA-binding protein (TDP-43). Here, we present initial evidence that in α-motoneurons the loss of normal nuclear TDP-43 expression is followed by the formation of phosphorylated TDP-43 aggregates (pTDP-43) within the cytoplasm, whereas in Betz cells, by contrast, the loss of normal nuclear TDP-43 expression remains mostly unaccompanied by the development of cytoplasmic aggregations...
October 18, 2016: Acta Neuropathologica
Henk-Jan Westeneng, Renée Walhout, Milou Straathof, Ruben Schmidt, Jeroen Hendrikse, Jan H Veldink, Martijn P van den Heuvel, Leonard H van den Berg
BACKGROUND: In patients with a C9orf72 repeat expansion (C9+), a neuroimaging phenotype with widespread structural cerebral changes has been found. We aimed to investigate the specificity of this neuroimaging phenotype in patients with amyotrophic lateral sclerosis (ALS). METHODS: 156 C9- and 14 C9+ patients with ALS underwent high-resolution T1-weighted MRI; a subset (n=126) underwent diffusion-weighted imaging. Cortical thickness, subcortical volumes and white matter integrity were compared between C9+ and C9- patients...
October 18, 2016: Journal of Neurology, Neurosurgery, and Psychiatry
Jésus Gonzalez-Bermejo, Capucine Morélot-Panzini, Marie-Laure Tanguy, Vincent Meininger, Pierre-François Pradat, Timothée Lenglet, Gaëlle Bruneteau, Nadine Le Forestier, Philippe Couratier, Nathalie Guy, Claude Desnuelle, Hélène Prigent, Christophe Perrin, Valérie Attali, Catherine Fargeot, Marie-Cécile Nierat, Catherine Royer, Fabrice Ménégaux, François Salachas, Thomas Similowski
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation...
November 2016: Lancet Neurology
Naoum P Issa, Samuel Frank, Raymond Roos, Betty Soliven, Vernon L Towle, Kourosh Rezania
INTRODUCTION: Simple laboratory tests of upper motor neuron involvement in amyotrophic lateral sclerosis (ALS) are not available. Intermuscular coherence has been shown to distinguish patients with primary lateral sclerosis, a pure upper motor neuron disorder, from normal subjects, suggesting it could be useful for assessing ALS. OBJECTIVE: To determine whether intermuscular coherence can distinguish ALS patients from normal subjects. METHODS: We measured biceps brachii and brachioradialis activity using surface electromyography while subjects held the elbow at flexion and the forearm in semi-pronation...
October 3, 2016: Muscle & Nerve
Paul Talman, Thi Duong, Steve Vucic, Susan Mathers, Svetha Venkatesh, Robert Henderson, Dominic Rowe, David Schultz, Robert Edis, Merrilee Needham, Richard Macdonnell, Pamela McCombe, Carol Birks, Matthew Kiernan
OBJECTIVE: To capture the clinical patterns, timing of key milestones and survival of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) within Australia. METHODS: Data were prospectively collected and were timed to normal clinical assessments. An initial registration clinical report form (CRF) and subsequent ongoing assessment CRFs were submitted with a completion CRF at the time of death. DESIGN: Prospective observational cohort study...
September 30, 2016: BMJ Open
Yohei Iguchi, Lara Eid, Martin Parent, Geneviève Soucy, Christine Bareil, Yuichi Riku, Kaori Kawai, Shinnosuke Takagi, Mari Yoshida, Masahisa Katsuno, Gen Sobue, Jean-Pierre Julien
Cytoplasmic TDP-43 aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here we investigated the role of exosomes in the secretion and propagation of TDP-43 aggregates. TDP-43 was detected in secreted exosomes from Neuro2a cells and primary neurons but not from astrocytes or microglia. Evidence is presented that protein aggregation and autophagy inhibition are factors that promote exosomal secretion of TDP-43. We also report that levels of exosomal TDP-43 full length and C-terminal fragment species are upregulated in human amyotrophic lateral sclerosis brains...
September 27, 2016: Brain: a Journal of Neurology
Mark R Cookson
Gene expression is regulated at many levels, including after generation of the primary RNA transcript from DNA but before translation into protein. Such post-translational gene regulation occurs via the action of a multitude of RNA binding proteins and include varied actions from splicing to regulation of association with the translational machinery. Primary evidence that such processes might contribute to disease mechanisms in neurodegenerative disorders comes from the observation of mutations in RNA binding proteins, particularly in diseases in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum and in some forms of ataxia and tremor...
September 23, 2016: Wiley Interdisciplinary Reviews. RNA
Alessia Sarica, Antonio Cerasa, Paola Valentino, Jason Yeatman, Maria Trotta, Stefania Barone, Alfredo Granata, Rita Nisticò, Paolo Perrotta, Franco Pucci, Aldo Quattrone
This work evaluates the potential in diagnostic application of a new advanced neuroimaging method, which delineates the profile of tissue properties along the corticospinal tract (CST) in amyotrophic lateral sclerosis (ALS), by means of diffusion tensor imaging (DTI). Twenty-four ALS patients and twenty-four demographically matched healthy subjects were enrolled in this study. The Automated Fiber Quantification (AFQ), a tool for the automatic reconstruction of white matter tract profiles, based on a deterministic tractography algorithm to automatically identify the CST and quantify its diffusion properties, was used...
September 23, 2016: Human Brain Mapping
Alberto Maggiani, Lucio Tremolizzo, Andrea Della Valentina, Laurent Mapelli, Silvia Sosio, Valeria Milano, Manuel Bianchi, Francesco Badi, Carolina Lavazza, Marco Grandini, Giovanni Corna, Paola Prometti, Christian Lunetta, Nilo Riva, Alessandra Ferri, Francesca Lanfranconi
BACKGROUND: Current interventions in amyotrophic lateral sclerosis (ALS) are focused on supporting quality of life (QoL) and easing pain with a multidisciplinary approach. OBJECTIVE: Primary aim of this pilot work assessed feasibility, safety, tolerability and satisfaction of osteopathic manual treatment (OMT) in 14 ALS outpatients. METHODS: Patients were randomized according to an initial single-blind design (12 weeks, T0-T1), in order to receive OMT (weekly for 4 weeks, and fortnightly for the following 8 weeks) versus usual-care (n=7 each group), followed by an OMT open period (T1-T2, once a week for 8 weeks, n=10)...
2016: Open Neurology Journal
Francisco J Carvajal, Hayley A Mattison, Waldo Cerpa
N-Methyl-D-aspartate receptors (NMDARs) have two opposing roles in the brain. On the one hand, NMDARs control critical events in the formation and development of synaptic organization and synaptic plasticity. On the other hand, the overactivation of NMDARs can promote neuronal death in neuropathological conditions. Ca(2+) influx acts as a primary modulator after NMDAR channel activation. An imbalance in Ca(2+) homeostasis is associated with several neurological diseases including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis...
2016: Neural Plasticity
Malcolm Proudfoot, Gustavo Rohenkohl, Andrew Quinn, Giles L Colclough, Joanne Wuu, Kevin Talbot, Mark W Woolrich, Michael Benatar, Anna C Nobre, Martin R Turner
Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15-30 Hz) power. Cortical beta-band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials...
September 13, 2016: Human Brain Mapping
Hyang Sook Seol, Sang Eun Lee, Joon Seon Song, Hye Yong Lee, Sojung Park, Inki Kim, Shree Ram Singh, Suhwan Chang, Se Jin Jang
Liver cancer is one of the common malignancies in many countries and an increasing cause of cancer death. Despite of that, there are few therapeutic options available with inconsistent outcome, raising a need for developing alternative therapeutic options. Through a drug repositioning screening, we identified and investigated the action mechanism of the Riluzole, an amyotrophic lateral sclerosis (ALS) drug, on hepatocellular carcinoma (HCC) therapy. Treatment of the Riluzole leads to a suppression of cell proliferation in liver primary cancer cells and cancer cell lines...
September 6, 2016: Cancer Letters
M R Hohmann, T Fomina, V Jayaram, N Widmann, C Förster, J Just, M Synofzik, B Schölkopf, L Schöls, M Grosse-Wentrup
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)...
2016: Progress in Brain Research
Roberto E Sica, Roberto Caccuri, Cecilia Quarracino, Francisco Capani
Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS) by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson's disease, Alzheimer's dementia, Huntington's dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction...
August 2016: Arquivos de Neuro-psiquiatria
Marianna Cortese, Trond Riise, Kjetil Bjørnevik, Alok Bhan, Elisabeth Farbu, Nina Grytten, Ineke Hogenesch, Rune Midgard, Cecilia Smith Simonsen, Wenche Telstad, Alberto Ascherio, Kjell-Morten Myhr
OBJECTIVE: To prospectively investigate potential signs of preclinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort. METHODS: We linked the cognitive performance of all Norwegian men born 1950-1995 who underwent conscription examination at age 18 to 19 years to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database...
October 2016: Annals of Neurology
Sandro Orrù, Paola Coni, Andrea Floris, Roberto Littera, Carlo Carcassi, Valeria Sogos, Carla Brancia
TAR deoxyribonucleic acid-binding protein 43 (TDP-43) is a key protein in the pathogenesis of amyoptrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Recent studies suggest that mutations in the TDP-43 coding gene, TARDBP, as well as variations in TDP-43 protein expression levels may disrupt the dynamics of stress granules (SGs). However, it remains unclear whether the pathogenetic effect of the TDP-43 protein is exerted at the cytoplasmic level, through direct participation to SG composition, or at nuclear level, through control of proteins essential to SG assembly...
August 22, 2016: Human Molecular Genetics
Nicholas J Silvestri, Gil I Wolfe, David Lacomis, Mark B Bromberg
The Guillain-Barré syndrome (GBS) is one of the few neuropathies well known to the general public, in part because of its association with swine flu vaccinations in 1976. GBS has again reached the general public with its possible association with Zika virus. The virus, borne by infected Aedes aegypti mosquitos, is being linked to birth defects when pregnant women are bitten and infected. There are early reports also linking GBS to Zika infection, which could expose a wider range of infected people to the neuropathy...
September 2016: Journal of Clinical Neuromuscular Disease
Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Cinzia Volonté
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. However, how to successfully balance neuroprotective versus neurotoxic actions by the use of antinflammatory agents is still under scrutiny. We have recently shown that the antihistamine clemastine, an FDA-approved drug, can influence the M1/M2 switch occurring in SOD1-G93A ALS microglia. METHODS: Here, we have chronically treated female SOD1-G93A mice with clemastine, evaluated disease progression and performed mice lumbar spinal cord analysis at symptomatic and end stage of the disease...
2016: Journal of Neuroinflammation
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