title: Defining brain volume cutoffs to identify clinically relevant atrophy in RRMS.
abstract: OBJECTIVE
  To define values of normalized brain volume (NBV) that can be categorized as low, medium, or high, according to baseline characteristics of relapsing-remitting multiple sclerosis (RRMS) patients.
  
  
  METHODS
  Expected NBV (eNBV) was calculated for each patient based on age, disease duration, sex, baseline Expanded Disability Status Scale (EDSS), and T2-lesion volume, entering these variables into a multiple regression model run on 2342 RRMS patients (pooled FREEDOMS/FREEDOMS-II population). According to the difference between their observed NBV and their eNBV, patients were classified as having low NBV, medium NBV, or high NBV. We evaluated whether these NBV categories were clinically meaningful by assessing correlation with disability worsening.
  
  
  RESULTS
  The distribution of differences between observed NBV and eNBV was used to categorize patients as having low NBV, medium NBV or high NBV. Taking the high-NBV group as reference, the hazard ratios (HRs) for 2-year disability worsening, adjusted for treatment effect, were 1.23 (95% confidence interval (CI): 0.92-1.63, p = 0.16) for the medium NBV and 1.75 (95% CI: 1.26-2.44, p = 0.001) for the low NBV. The predictive value of NBV groups was preserved over 4 years. Treatment effect appeared more evident in low-NBV patients (HR = 0.58) than in medium-NBV (HR = 0.72) and in high-NBV (HR = 0.80) patients; however, the difference was not significant ( p = 0.57).
  
  
  CONCLUSIONS
  RRMS patients can be categorized into disability risk groups based on individual eNBV values according to baseline demographics and clinical characteristics.
authors.affiliation: Biostatistics Unit, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Sormani
authors.affiliation: Neurological Clinic and Polyclinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Medical Image Analysis Center (MIAC), University Hospital Basel, Basel, Switzerland.
authors.forename: Ernst-Wilhelm
authors.initials: EW
authors.lastname: Radue
authors.affiliation: Neurological Institute, The Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cohen
authors.affiliation: Department of Radiology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: Department of Neurology, DKD Helios Klinik Wiesbaden, Wiesbaden, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Sprenger
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Piani Meier
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häring
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Davorka
authors.initials: D
authors.lastname: Tomic
authors.affiliation: University of Siena, Siena, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Stefano
mesh_terms: D000293:Adolescent; D000328:Adult; D001284:Atrophy / Q000188:drug therapy; D001921:Brain / Q000473:pathology*; D004185:Disability Evaluation; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000473:pathology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents
keywords: Disability worsening; fingolimod; multiple sclerosis; normalized brain volume