title: Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis.
abstract: OBJECTIVE
  White matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increases if WMV decreases and the cortical surface area remains constant.
  
  
  METHODS
  In total, 95 participants were enrolled: 30 patients with early and advanced relapsing-remitting MS; 30 age-matched control subjects; 30 patients with Alzheimer's disease (AD) and 5 patients with clinically isolated syndrome (CIS).
  
  
  RESULTS
  29/30 MS and 5/5 CIS patients showed lower WMV than expected from their intracranial volume (average reduction 13.0%, P < 10(- 10)), while the cortical surface area showed no significant differences compared with controls. The estimated WMV reductions were correlated with an increase in cortical curvature (R = 0.62, P = 0.000001). Discriminant analysis revealed that the curvature increase was highly specific for the MS and CIS groups (96.7% correct assignments between MS and control groups) and was significantly correlated with reduction of white matter fractional anisotropy, as determined by diffusion tensor imaging and the Expanded Disability Status Scale. As expected by the predominant gray and WM degeneration in AD, no systematic curvature increase was observed in AD.
  
  
  CONCLUSIONS
  Whole-brain-averaged cortical extrinsic curvature appears to be a specific and quantitative marker for a WMV-cortex disproportionality and allows us to assess "pure" WMA without being confounded by intracranial volume. WMA seems to be a characteristic symptom in early MS and can already occur in patients with CIS and should thus be considered in future MS research and clinical studies.
authors.affiliation: Department of Neurology, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Deppe
authors.affiliation: Department of Neurology, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Marinell
authors.affiliation: Department of Neurology, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Krämer
authors.affiliation: Department of Neurology, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Duning
authors.affiliation: Department of Neurology, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ruck
authors.affiliation: Department of Neurology, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Ole J
authors.initials: OJ
authors.lastname: Simon
authors.affiliation: Department of Neurology, Rhine Main Neuroscience Network, Johannes Gutenberg University Medical Centre Mainz, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.affiliation: Department of Neurology, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: Department of Neurology, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology*; D016880:Anisotropy; D001284:Atrophy; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000473:pathology*; D003711:Demyelinating Diseases / 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 / Q000473:pathology*; D066127:White Matter / Q000473:pathology*; D055815:Young Adult
keywords: 3D, three-dimensional; CI, confidence interval; CIS, clinically isolated syndrome; Cortex; Cortical curvature; DTI, diffusion tensor imaging; EDSS, Expanded Disability Status Scale; EVAL, Münster Neuroimaging Evaluation System; FA, fractional anisotropy; FOV, field of view; GM, gray matter; GMV, gray matter volume; GRAPPA, generalized autocalibrating partially parallel acquisition; ICV, intracranial volume; Imaging; MRI; Multiple sclerosis; ROI, region of interest; SD, standard deviation; TE, echo time; TR, repetition time; TSE, turbo spin-echo; WM, white matter; WMV, white matter volume; eWMV, estimated white matter volume; ΔWMV, WMV − eWMV