title: Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.
abstract: OBJECTIVE
  To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS).
  
  
  METHODS
  A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression.
  
  
  RESULTS
  Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products.
  
  
  CONCLUSIONS
  Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression.
  
  
  BACKGROUND
  NIHRID6160.
authors.affiliation: Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK.
authors.forename: Ching-Hua
authors.initials: CH
authors.lastname: Lu
authors.affiliation: Department of Neuroinflammation, UCL Institute of Neurology, London, UK.
authors.forename: Axel
authors.initials: A
authors.lastname: Petzold
authors.affiliation: Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Topping
authors.affiliation: Basildon and Thurrock University Hospitals NHS Foundation Trust, Essex, UK.
authors.forename: Kezia
authors.initials: K
authors.lastname: Allen
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Corrie
authors.initials: C
authors.lastname: Macdonald-Wallis
authors.affiliation: National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Clarke
authors.affiliation: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Pearce
authors.affiliation: Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Jens
authors.initials: J
authors.lastname: Kuhle
authors.affiliation: Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fratta
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Sidle
authors.affiliation: Clinical Trial Unit, Musgrove Park Hospital, Taunton, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Fish
authors.affiliation: National Hospital for Neurology and Neurosurgery, London, UK Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Orrell
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Howard
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.affiliation: Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK Basildon and Thurrock University Hospitals NHS Foundation Trust, Essex, UK North-East London and Essex MND Care and Research Centre, London, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Malaspina
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000097:blood* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D016900:Neurofilament Proteins / Q000097:blood*
chemical_list: D001323:Autoantibodies; D016900:Neurofilament Proteins
keywords: ALS; Motor Neuron Disease; Neuroimmunology