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