title: Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis.
abstract: OBJECTIVE
  We investigated the determinants and clinical correlations of MRI-detected brain volume loss (BVL) among patients with relapsing-remitting multiple sclerosis from the phase 3 trials of fingolimod: FREEDOMS, FREEDOMS II, and TRANSFORMS.
  
  
  METHODS
  Post hoc analyses were conducted in the intent-to-treat populations from each trial and in a combined dataset of 3,635 patients from the trials and their extensions. The relationship between brain volume changes and demographic, clinical, and MRI parameters was studied in pairwise correlations (Pearson) and in multiple regression models. The relative frequency of confirmed disability progression was evaluated in the combined dataset by strata of concurrent BVL at up to 4 years.
  
  
  RESULTS
  Increasing age, disease duration, T2 lesion volume, T1-hypointense lesion volume, and disability were associated with reduced brain volume (p < 0.001, all). The strongest individual baseline predictors of on-study BVL were T2 lesion volume, gadolinium-enhancing lesion count, and T1-hypointense lesion volume (p < 0.01, all). During each study, BVL correlated most strongly with cumulative gadolinium-enhancing lesion count, new/enlarged T2 lesion count (p < 0.001, both), and number of confirmed on-study relapses (p < 0.01). Over 4 years in the combined dataset (mean exposure to study drug, 2.4 years), confirmed disability progression was most frequent in patients with greatest BVL.
  
  
  CONCLUSIONS
  Rate of BVL in patients during the fingolimod trials correlated with disease severity at baseline and new disease activity on study, and was associated with worsening disability.
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
authors: Ernst-Wilhelm
authors: EW
authors: Radue
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
authors: Frederik
authors: F
authors: Barkhof
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH. ludwig.kappos@usb.ch.
authors: Ludwig
authors: L
authors: Kappos
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
authors: Till
authors: T
authors: Sprenger
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
authors: Dieter A
authors: DA
authors: Häring
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
authors: Ana
authors: A
authors: de Vera
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
authors: Philipp
authors: P
authors: von Rosenstiel
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
authors: Jeremy R
authors: JR
authors: Bright
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
authors: Gordon
authors: G
authors: Francis
authors: From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
authors: Jeffrey A
authors: JA
authors: Cohen
mesh_terms: D001921:Brain / Q000473:pathology*; D004311:Double-Blind Method; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000639:trends; D008297:Male; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000188:drug therapy*; D009929:Organ Size; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
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