title: Lessons of ALS imaging: Pitfalls and future directions - A critical review.
abstract: BACKGROUND
  While neuroimaging in ALS has gained unprecedented momentum in recent years, little progress has been made in the development of viable diagnostic, prognostic and monitoring markers.
  
  
  OBJECTIVE
  To identify and discuss the common pitfalls in ALS imaging studies and to reflect on optimal study designs based on pioneering studies.
  
  
  METHODS
  A "PubMed"-based literature search on ALS was performed based on neuroimaging-related keywords. Study limitations were systematically reviewed and classified so that stereotypical trends could be identified.
  
  
  RESULTS
  Common shortcomings, such as relatively small sample sizes, statistically underpowered study designs, lack of disease controls, poorly characterised patient cohorts and a large number of conflicting studies, remain a significant challenge to the field. Imaging data of ALS continue to be interpreted at a group-level, as opposed to meaningful individual-patient inferences.
  
  
  CONCLUSIONS
  A systematic, critical review of ALS imaging has identified stereotypical shortcomings, the lessons of which should be considered in the design of future prospective MRI studies. At a time when large multicentre studies are underway a candid discussion of these factors is particularly timely.
authors.affiliation: Academic Unit of Neurology, Trinity College Dublin, Room 5.43, Biomedical Sciences Building, Pearse Street, Dublin 2, Ireland.
authors.forename: Peter
authors.initials: P
authors.lastname: Bede
authors.affiliation: Academic Unit of Neurology, Trinity College Dublin, Room 5.43, Biomedical Sciences Building, Pearse Street, Dublin 2, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000000981:diagnostic imaging* / Q000473:pathology*; D016477:Artifacts; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology*; D005544:Forecasting; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D059906:Neuroimaging / Q000379:methods* / Q000639:trends; D011877:Radionuclide Imaging; D012107:Research Design / Q000639:trends; D018401:Sample Size
keywords: AD, axial diffusivity; Amyotrophic lateral sclerosis; Biomarker; C9orf72, chromosome 9 open reading frame 72; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, mean diffusivity; MEG, magnetoencephalography; MRI; MRS, magnetic resonance spectroscopy; MUNE, motor unit number estimation; PET; PET, positron emission tomography; PNS, peripheral nervous system; RD, radial diffusivity; ROI, region of interest; SPECT, single photon emission computed tomography; Spectroscopy; TMS, transcranial magnetic stimulation; VBM, voxel-based morphometry