title: Association of Cortical Lesion Burden on 7-T Magnetic Resonance Imaging With Cognition and Disability in Multiple Sclerosis.
abstract: OBJECTIVE
  Cortical lesions (CLs) contribute to physical and cognitive disability in multiple sclerosis (MS). Accurate methods for visualization of CLs are necessary for future clinical studies and therapeutic trials in MS.
  
  
  OBJECTIVE
  To evaluate the clinical relevance of measures of CL burden derived from high-field magnetic resonance imaging (MRI) in MS.
  
  
  METHODS
  An observational clinical imaging study was conducted at an academic MS center. Participants included 36 individuals with MS (30 relapsing-remitting, 6 secondary or primary progressive) and 15 healthy individuals serving as controls. The study was conducted from March 10, 2010, to November 23, 2012, and analysis was performed from June 1, 2011, to September 30, 2014. Seven-Tesla MRI of the brain was performed with 0.5-mm isotropic resolution magnetization-prepared rapid acquisition gradient echo (MPRAGE) and whole-brain, 3-dimensional, 1.0-mm isotropic resolution magnetization-prepared, fluid-attenuated inversion recovery (MPFLAIR). Cortical lesions, seen as hypointensities on MPRAGE, were manually segmented. Lesions were classified as leukocortical, intracortical, or subpial. Images were segmented using the Lesion-TOADS (Topology-Preserving Anatomical Segmentation) algorithm, and brain structure volumes and white matter (WM) lesion volume were reported. Volumes were normalized to intracranial volume.
  
  
  METHODS
  Physical disability was measured by the Expanded Disability Status Scale (EDSS). Cognitive disability was measured with the Minimal Assessment of Cognitive Function in MS battery.
  
  
  RESULTS
  Cortical lesions were noted in 35 of 36 participants (97%), with a median of 16 lesions per participant (range, 0-99). Leukocortical lesion volume correlated with WM lesion volume (ρ = 0.50; P = .003) but not with cortical volume; subpial lesion volume inversely correlated with cortical volume (ρ = -0.36; P = .04) but not with WM lesion volume. Total CL count and volume, measured as median (range), were significantly increased in participants with EDSS scores of 5.0 or more vs those with scores less than 5.0 (count: 29 [11-99] vs 13 [0-51]; volume: 2.81 × 10-4 [1.30 × 10-4 to 7.90 × 10-4] vs 1.50 × 10-4 [0 to 1.01 × 10-3]) and in cognitively impaired vs unimpaired individuals (count: 21 [0-99] vs 13 [1-54]; volume: 3.51 × 10-4 [0 to 1.01 × 10-4] vs 1.19 × 10-4 [0 to 7.17 × 10-4]). Cortical lesion volume correlated with EDSS scores more robustly than did WM lesion volume (ρ = 0.59 vs 0.36). Increasing log[CL volume] conferred a 3-fold increase in the odds of cognitive impairment (odds ratio [OR], 3.36; 95% CI, 1.07-10.59; P = .04) after adjustment for age and sex and a 14-fold increase in odds after adjustment for WM lesion volume and atrophy (OR, 14.26; 95% CI, 1.06-192.37; P = .045). Leukocortical lesions had the greatest effect on cognition (OR for log [leukocortical lesion volume], 9.65; 95% CI, 1.70-54.59, P = .01).
  
  
  CONCLUSIONS
  This study provides in vivo evidence that CLs are associated with cognitive and physical disability in MS and that leukocortical and subpial lesion subtypes have differing clinical relevance. Quantitative assessments of CL burden on high-field MRI may further our understanding of the development of disability and progression in MS and lead to more effective treatments.
authors.affiliation: Department of Neurology, School of Medicine, University of Maryland, Baltimore2Department of Neurology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Harrison
authors.affiliation: Center for Neuroscience and Regenerative Medicine, Henry Jackson Foundation, Bethesda, Maryland.
authors.forename: Snehashis
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Neurology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland4Department of Neurology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Oh
authors.affiliation: Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Izlem
authors.initials: I
authors.lastname: Izbudak
authors.affiliation: Center for Neuroscience and Regenerative Medicine, Henry Jackson Foundation, Bethesda, Maryland.
authors.forename: Dzung
authors.initials: D
authors.lastname: Pham
authors.affiliation: Department of Psychological and Brain Sciences, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Susan
authors.initials: S
authors.lastname: Courtney
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Brian
authors.initials: B
authors.lastname: Caffo
authors.affiliation: Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, Maryland8F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland.
authors.forename: Craig K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, Maryland8F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: van Zijl
authors.affiliation: Department of Neurology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000473:pathology*; D003072:Cognition Disorders / Q000209:etiology*; D004185:Disability Evaluation; D006233:Persons with Disabilities; D005260:Female; D007839:Functional Laterality; D006801:Humans; D021621:Imaging, Three-Dimensional; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications* / Q000473:pathology*; D009483:Neuropsychological Tests; D014706:Verbal Learning