Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials
TLDR
Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of life.Abstract:
Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot in the 1870s, is an age-related disorder that leads to degeneration of motor neurons. The disease begins focally in the central nervous system and then spreads relentlessly. The clinical diagnosis, defined by progressive signs and symptoms of upper and lower motor neuron dysfunction, is confirmed by electromyography. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of respiratory muscle weakness less than 3 years from symptom-onset. Like other age-related neurodegenerative diseases, ALS has genetic and environmental triggers. Of the five to 10% of cases that are inherited, mutations have been discovered for a high proportion. In addition to genetic factors, age, tobacco use, and athleticism may contribute to sporadic ALS, but important etiologies are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. The mechanisms leading to disease propagation in the brain are a current focus of research. To date, one medication, riluzole, licensed in 1996, has been proved to prolong survival in ALS. Numerous clinical trials have so far been unable to identify another neuroprotective agent. Researchers now aim to slow disease progression by targeting known pathophysiological pathways or genetic defects. Current approaches are directed at muscle proteins such as Nogo, energetic balance, cell replacement, and abnormal gene products resulting from mutations. Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of life. Palliative care programs such as hospice give emotional and physical support to patients and families throughout much of the disease course.read more
Citations
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Journal ArticleDOI
Amyotrophic Lateral Sclerosis: A Focus on Disease Progression
Ana C. Calvo,Raquel Manzano,Deise M. F. Mendonça,María Jesús Muñoz,Pilar Zaragoza,Rosario Osta +5 more
TL;DR: The progression of the disease is discussed from the viewpoint of the potential biomarkers described to date in human and animal model samples and potential therapeutic strategies for ALS treatment and future, innovative perspectives are considered.
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Altered Proteins in the Aging Brain.
TL;DR: Altered proteins are common in the brains of cognitively unimpaired aged subjects; this should be considered while developing diagnostic biomarkers, particularly for identifying subjects at early stages of neurodegenerative diseases.
Journal ArticleDOI
Glia in the pathogenesis of neurodegenerative diseases
Alexei Verkhratsky,Alexei Verkhratsky,Vladimir Parpura,Vladimir Parpura,Marcela Pekna,Marcela Pekna,Milos Pekny,Milos Pekny,Michael V. Sofroniew +8 more
TL;DR: The mounting evidence supporting a change away from the perception of reactive glial responses merely as secondary detrimental processes that exacerbate the course of neurological disorders is considered, in favour of an emerging contemporary view of glial pathological responses as complex and multistaged defensive processes that also have the potential for dysfunction.
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Translocator Protein-18 kDa (TSPO) Positron Emission Tomography (PET) Imaging and Its Clinical Impact in Neurodegenerative Diseases.
Anne-Claire Dupont,Bérenger Largeau,Maria Joao Ribeiro,Denis Guilloteau,Claire Tronel,Nicolas Arlicot +5 more
TL;DR: New and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research are exposed by exploring microglia’s role and interactions with other cells in brain parenchyma.
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The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis
TL;DR: Given the role of oxidative stress in ALS, targeted antioxidant treatments could be a promising therapeutic approach and the complex nature of ALS and failure of monotherapies suggest that an antioxidant therapy should be accompanied by anti-inflammatory interventions to enhance the restoration of the redox balance.
References
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Journal ArticleDOI
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Journal ArticleDOI
El Escorial revisited : revised criteria for the diagnosis of amyotrophic lateral sclerosis
TL;DR: The criteria described below represent the result of a three-day workshop, convened at Airlie Conference Center, Warrenton, Virginia on 2–4 April, 1998 by the World Federation of Neurology Research Committee on Motor Neuron Diseases, and are placed on the WFN ALS website.
Journal ArticleDOI
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
Thomas J. Kwiatkowski,D. A. Bosco,D. A. Bosco,A. L. LeClerc,A. L. LeClerc,Eric Tamrazian,Charles R. Vanderburg,Carsten Russ,Carsten Russ,A. Davis,James M. Gilchrist,E. J. Kasarskis,Theodore L. Munsat,Paul N. Valdmanis,Guy A. Rouleau,Betsy A. Hosler,Pietro Cortelli,P. J. De Jong,Yuko Yoshinaga,Jonathan L. Haines,Margaret A. Pericak-Vance,Jianhua Yan,Nicola Ticozzi,Nicola Ticozzi,Nicola Ticozzi,Teepu Siddique,Diane McKenna-Yasek,Peter C. Sapp,Peter C. Sapp,H R Horvitz,John Landers,John Landers,Robert H. Brown,Robert H. Brown +33 more
TL;DR: Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
Journal ArticleDOI
A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis
TL;DR: The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset, according to a prospective, double-blind, placebo-controlled trial in 155 outpatients with Amyotrophicateral sclerosis.
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