title: What drives MRI-measured cortical atrophy in multiple sclerosis?
abstract: BACKGROUND
  Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure in multiple sclerosis (MS) studies. However, the underlying histopathology of cortical volume measures is unknown.
  
  
  OBJECTIVE
  We investigated the histopathological substrate of MRI-measured cortical volume in MS using combined post-mortem imaging and histopathology.
  
  
  METHODS
  MS brain donors underwent post-mortem whole-brain in-situ MRI imaging. After MRI, tissue blocks were systematically sampled from the superior and inferior frontal gyrus, anterior cingulate gyrus, inferior parietal lobule, and superior temporal gyrus. Histopathological markers included neuronal, axonal, synapse, astrocyte, dendrite, myelin, and oligodendrocyte densities. Matched cortical volumes from the aforementioned anatomical regions were measured on the MRI, and used as outcomes in a nested prediction model.
  
  
  RESULTS
  Forty-five tissue blocks were sampled from 11 MS brain donors. Mean age at death was 68±12 years, post-mortem interval 4±1 hours, and disease duration 35±15 years. MRI-measured regional cortical volumes varied depending on anatomical region. Neuronal density, neuronal size, and axonal density were significant predictors of GM volume.
  
  
  CONCLUSIONS
  In patients with long-standing disease, neuronal and axonal pathology are the predominant pathological substrates of MRI-measured cortical volume in chronic MS.
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: Popescu
authors.affiliation: Department of Anatomy and Neurosciences, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands r.klaver@vumc.nl.
authors.forename: R
authors.initials: R
authors.lastname: Klaver
authors.affiliation: Department of Anatomy and Neurosciences, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Voorn
authors.affiliation: Department of Anatomy and Neurosciences, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Galis-de Graaf
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: D L
authors.initials: DL
authors.lastname: Knol
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: J W R
authors.initials: JW
authors.lastname: Twisk
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Versteeg
authors.affiliation: Department of Anatomy and Neurosciences, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Schenk
authors.affiliation: Department of Pathology, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Van der Valk
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: H E
authors.initials: HE
authors.lastname: De Vries
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands/Department of Physics and Medical Technology, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Vrenken
authors.affiliation: Department of Anatomy and Neurosciences, VU University Medical Center, Neuroscience Campus Amsterdam, The Netherlands.
authors.forename: J J G
authors.initials: JJ
authors.lastname: Geurts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001284:Atrophy / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000473:pathology; D010296:Parietal Lobe / Q000473:pathology*
keywords: MRI; Multiple sclerosis; brain atrophy; gray matter; histopathology; neurodegeneration