title: Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant.
abstract: Grey matter atrophy is common in multiple sclerosis. However, in contrast with other neurodegenerative diseases, it is unclear whether grey matter atrophy in multiple sclerosis is a diffuse 'global' process or develops, instead, according to distinct anatomical patterns. Using source-based morphometry we searched for anatomical patterns of co-varying cortical thickness and assessed their relationships with white matter pathology, physical disability and cognitive functioning. Magnetic resonance imaging was performed at 3 T in 208 patients with long-standing multiple sclerosis (141 females; age = 53.7 ± 9.6 years; disease duration = 20.2 ± 7.1 years) and 60 age- and sex-matched healthy controls. Spatial independent component analysis was performed on cortical thickness maps derived from 3D T1-weighted images across all subjects to identify co-varying patterns. The loadings, which reflect the presence of each cortical thickness pattern in a subject, were compared between patients with multiple sclerosis and healthy controls with generalized linear models. Stepwise linear regression analyses were used to assess whether white matter pathology was associated with these loadings and to identify the cortical thickness patterns that predict measures of physical and cognitive dysfunction. Ten cortical thickness patterns were identified, of which six had significantly lower loadings in patients with multiple sclerosis than in controls: the largest loading differences corresponded to the pattern predominantly involving the bilateral temporal pole and entorhinal cortex, and the pattern involving the bilateral posterior cingulate cortex. In patients with multiple sclerosis, overall white matter lesion load was negatively associated with the loadings of these two patterns. The final model for physical dysfunction as measured with Expanded Disability Status Scale score (adjusted R(2) = 0.297; P < 0.001) included the predictors age, overall white matter lesion load, the loadings of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R(2) = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal-appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy.
authors.affiliation: 1 Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands 2 Department of Physics and Medical Technology, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands m.steenwijk@vumc.nl.
authors.forename: Martijn D
authors.initials: MD
authors.lastname: Steenwijk
authors.affiliation: 3 Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Jeroen J G
authors.initials: JJ
authors.lastname: Geurts
authors.affiliation: 1 Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands 3 Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Marita
authors.initials: M
authors.lastname: Daams
authors.affiliation: 4 Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Betty M
authors.initials: BM
authors.lastname: Tijms
authors.affiliation: 1 Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Alle Meije
authors.initials: AM
authors.lastname: Wink
authors.affiliation: 4 Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Lisanne J
authors.initials: LJ
authors.lastname: Balk
authors.affiliation: 4 Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Prejaas K
authors.initials: PK
authors.lastname: Tewarie
authors.affiliation: 4 Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Bernard M J
authors.initials: BM
authors.lastname: Uitdehaag
authors.affiliation: 1 Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: 1 Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands 2 Department of Physics and Medical Technology, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vrenken
authors.affiliation: 2 Department of Physics and Medical Technology, Neuroscience Campus Amsterdam, VU University Medical Centre, The Netherlands.
authors.forename: Petra J W
authors.initials: PJ
authors.lastname: Pouwels
mesh_terms: D001284:Atrophy / Q000473:pathology*; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000473:pathology*; D003072:Cognition Disorders / Q000150:complications / Q000473:pathology; D004185:Disability Evaluation; D005260:Female; D066128:Gray Matter / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009103:Multiple Sclerosis / Q000150:complications / Q000473:pathology*; D059906:Neuroimaging; D066127:White Matter / Q000473:pathology
keywords: MRI; grey matter; multiple sclerosis; neurodegeneration; white matter