title: Mitochondrial abnormalities and low grade inflammation are present in the skeletal muscle of a minority of patients with amyotrophic lateral sclerosis; an observational myopathology study.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a primary progressive neurodegenerative disease characterised by neuronal loss of lower motor neurons (in the spinal cord and brainstem) and/or upper motor neurons (in the motor cortex) and subsequent denervation atrophy of skeletal muscle.
  
  
  OBJECTIVE
  A comprehensive examination of muscle pathology from a cohort of clinically confirmed ALS patients, including an investigation of inflammation, complement activation, and deposition of abnormal proteins in order to compare them with findings from an age-matched, control group.
  
  
  METHODS
  31 muscle biopsies from clinically confirmed ALS patients and 20 normal controls underwent a comprehensive protocol of histochemical and immunohistochemical stains, including HLA-ABC, C5b-9, p62, and TDP-43.
  
  
  RESULTS
  Neurogenic changes were confirmed in 30/31 ALS cases. In one case, no neurogenic changes could be detected. Muscle fibre necrosis was seen in 5/31 cases and chronic mononuclear inflammatory cell infiltration in 5/31 (2 of them overlapped with those showing muscle necrosis). In four biopsies there was an increase in the proportion of cytochrome oxidase (COX) negative fibres (2-3%). p62 faintly stained cytoplasmic bodies in eight cases and none were immunoreactive to TDP-43.
  
  
  CONCLUSIONS
  This large series of muscle biopsies from patients with ALS demonstrates neurogenic atrophy is a nearly uniform finding and that mild mitochondrial abnormalities and low-grade inflammation can be seen and do not rule out the diagnosis of ALS. These findings could lend support to the notion that ALS is a complex and heterogeneous disorder.
authors.affiliation: Neuropathology, Neuroscience Academic Building, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK. safa.al-sarraj@nhs.net.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: Neuropathology, Neuroscience Academic Building, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK. Andrewking@nhs.net.
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.affiliation: Biopharm Translational Medicine, GSK, Stevenage, UK. matthew.s.cleveland@gsk.com.
authors.forename: Matt
authors.initials: M
authors.lastname: Cleveland
authors.affiliation: Département des Maladies du Système Nerveux, APHP, Reseau SLA IDF Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Laboratoire d'Imagerie Biomédicale (LIB), Paris, F-75005, France. pierre-francois.pradat@psl.aphp.fr.
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Pradat
authors.affiliation: Department of Neurology, Johns Hopkins School of Medicine, 1800 Orleans Street, Baltimore, MD, USA. acorse@jhmi.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Corse
authors.affiliation: Department of Neurology, Johns Hopkins School of Medicine, 1800 Orleans Street, Baltimore, MD, USA. jrothstein@jhmi.edu.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
authors.affiliation: Division of Medicine (Neurology), Brighton and Sussex Medical School, Trafford Centre for biomedical Research, Falmer, Brighton, BN1 9RY, UK. PNigel.Leigh@kcl.ac.uk.
authors.forename: Peter Nigel
authors.initials: PN
authors.lastname: Leigh
authors.affiliation: Biopharm Translational Medicine, GSK, Stevenage, UK. bams.5.abila@gsk.com.
authors.forename: Bams
authors.initials: B
authors.lastname: Abila
authors.affiliation: Biopharm Translational Medicine, GSK, Stevenage, UK. Stewart.A.Bates@gsk.com.
authors.forename: Stewart
authors.initials: S
authors.lastname: Bates
authors.affiliation: Novartis Oncology Translational Medicine, Basel, Switzerland. jens.wuerthner@novartis.com.
authors.forename: Jens
authors.initials: J
authors.lastname: Wurthner
authors.affiliation: Département des Maladies du Système Nerveux, APHP, Reseau SLA IDF Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Laboratoire d'Imagerie Biomédicale (LIB), Paris, F-75005, France. vincent.meininger@upmc.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D001706:Biopsy; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000276:immunology* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology*; D009336:Necrosis; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C118585:P62 protein, human; D016601:RNA-Binding Proteins; C000598624:TARDBP protein, human; D003576:Electron Transport Complex IV