Elsevier

NeuroImage

Volume 34, Issue 2, 15 January 2007, Pages 509-517
NeuroImage

Focal cortical atrophy in multiple sclerosis: Relation to lesion load and disability

https://doi.org/10.1016/j.neuroimage.2006.10.006Get rights and content

Abstract

Multiple sclerosis (MS) is thought to predominantly affect white matter (WM). Recently, however, loss of cortical gray matter has also been described. Little is known about the cause of cortical atrophy in MS, whether it occurs early in the disease course, and whether it affects all cortical regions equally or if there is a preferential pattern of focal cortical atrophy. An automated method was used to compute the thickness at every vertex of the cortical surface of the brains of 425 early relapsing–remitting MS patients. We correlated cortical thickness with the WM lesion load and the Expanded Disability Status Scale score. Mean cortical thickness correlated with WM lesion load and disability. The correlations of cortical thickness with total lesion load and disability were most significant in cingulate gyrus, insula, and associative cortical regions. Conversely, primary sensory, visual, and motor areas showed a less significant relationship. The highest amount of atrophy per lesion volume or disability scale unit was in the anterior cingulate cortex. This study confirms the relation between cortical atrophy, WM lesion load, and disability in MS, and suggests that cortical atrophy occurs even in MS patients with only mild disability. Most interestingly, we show a specific regional pattern of focal atrophy in MS that is distinctively different from the one in normal aging. The predilection of the atrophic process for areas that are heavily inter-connected with other brain regions suggests that interruption of WM tracts by MS plaques contributes, at least in part, to the development of cortical atrophy.

Introduction

Multiple sclerosis (MS) is traditionally described as a multifocal inflammatory demyelinating disease primarily affecting the white matter (WM) of the central nervous system with relative preservation of axons and cell bodies. However, more recent studies have demonstrated the presence of gray matter (GM) lesions (Peterson et al., 2001, Geurts et al., 2005) and brain atrophy (Chard et al., 2002, Anderson et al., 2006). Total brain atrophy can be viewed as a surrogate marker of the destructive pathological processes taking place in MS and can be observed with magnetic resonance imaging (MRI) by measuring the brain parenchymal fraction, a normalized measure that represents the sum of both gray matter (GM) and WM atrophy (Chard et al., 2002). In addition to establishing global brain atrophy as a pathological feature of the disease, studies have focused separately on the atrophy of cortical GM by measuring decreases in normalized cortical volumes (De Stefano et al., 2003), by means of an ordinal visual scale (Bakshi et al., 2001), or by directly measuring cortical thickness in vivo (Sailer et al., 2003, Chen et al., 2004). MS-related cerebral atrophy appears to be clinically relevant as it correlates with measures of both disability (Bakshi et al., 2001, De Stefano et al., 2003) and disease progression (Hardmeier et al., 2003, Kalkers et al., 2002).

To date, little is known about the mechanisms involved in cortical atrophy in MS, and whether it is a diffuse process affecting all cortical regions equally or if there is a preferential pattern of focal cortical atrophy. Studies designed to investigate focal changes in cortical thickness in vivo, and their relation to clinical parameters in large groups of MS patients are lacking, possibly because of the technical challenges involved in accurately measuring the thickness of the cortex across the entire brain with its complex folding patterns.

In the present study, an automated method (Lerch et al., 2005) was used to compute the thickness at every vertex of the cortical surface of the brains of 425 relapsing–remitting MS patients. Cortical thickness is one dimension of the cortical volume, the other being surface area. One of the advantages of using cortical thickness as a measure is that it makes a statistical parametric mapping analysis possible and no longer requires the specification of regions of interest.

The novelty of the present study is to investigate cortical changes in a large group of MS patients by measuring the thickness throughout the entire cortex, thus offering a direct quantitative index of cortical atrophy that is more meaningful than GM density or concentration as used in voxel-based morphometry (Ashburner and Friston, 2000).

Cortical atrophy as defined here refers to a loss of GM that results in thinning of the cortex. The goal of this study was to investigate the relation between overall as well as focal cortical atrophy and both the total WM lesion load (TWMLL) and disability in a large group of relapsing–remitting MS patients.

Section snippets

Patients and methods

We studied 425 patients with clinically definite relapsing–remitting MS (Poser et al., 1983) (228 males; mean age = 39 years; SD = 6; range = 21–48 years) who had undergone yearly MRI acquisition and clinical evaluation for 2 years as part of a phase III clinical trial. The study, designed to study the effects of an oral formulation of bovine myelin (MyloralTM, Autoimmune Inc., Lexington MA) (Weiner, 1997, Charil et al., 2003), revealed no differences in frequency of relapses or progression of

Results

The MS patients were mildly disabled, with a median EDSS score of 2 (range 0–8). Only 12.7% had an EDSS score greater or equal to 4.5 at the time of the 24-month MRI exam. The mean relative TWMLL was 14.3 cm3 (SD = 14.3 cm3, range = 0.2–78.6 cm3).

Discussion

The fully automated method used in the present study has been previously applied to the study of brain development (Lerch et al., 2006, Shaw et al., 2006a, Shaw et al., 2006b) and Alzheimer's disease (Lerch et al., 2005), and now, for the first time, to 425 relapsing–remitting MS patients in order to measure cortical thickness over the entire brain. We investigated the relation between both overall and focal cortical thickness and the TWMLL, and the EDSS.

We observed a significant negative

Acknowledgments

The MRI and clinical database was collected as part of a phase III clinical trial of oral myelin (Myloral) for treatment of multiple sclerosis, financed by Autoimmune Inc. of Boston, MA. The analysis reported in this study has been supported in part by NIH Human Brain Project award P01MH52176-06 to the International Consortium for Brain Mapping (ICBM) and by Canadian Institutes of Health Research Grants MOP 37754, MOP 14780, and MGC 13792 awarded to Evans and Dagher. Dr. Dagher is supported by

References (39)

  • R. Bakshi et al.

    Regional brain atrophy is associated with physical disability in multiple sclerosis: semiquantitative magnetic resonance imaging and relationship to clinical findings

    J. Neuroimaging

    (2001)
  • L. et al.

    Subpial demyelination in the cerebral cortex of multiple sclerosis patients

    J. Neuropathol. Exp. Neurol.

    (2003)
  • D.T. Chard et al.

    Brain atrophy in clinically early relapsing–remitting multiple sclerosis

    Brain

    (2002)
  • D.L. Collins et al.

    Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space

    J. Comput. Assist. Tomogr.

    (1994)
  • G.R. Cutter et al.

    Development of a multiple sclerosis functional composite as a clinical trial outcome measure

    Brain

    (1999)
  • N. De Stefano et al.

    Evidence of early cortical atrophy in MS: relevance to white matter changes and disability

    Neurology

    (2003)
  • A. Eastwood et al.

    Disappointing results from clinical trial of oral myelin for relapsing–remitting multiple sclerosis

  • Y. Ge et al.

    Brain atrophy in relapsing–remitting multiple sclerosis: fractional volumetric analysis of gray matter and white matter

    Radiology

    (2001)
  • J.J. Geurts et al.

    Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging

    Radiology

    (2005)
  • Cited by (0)

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