Elsevier

NeuroImage

Volume 23, Issue 3, November 2004, Pages 1168-1175
NeuroImage

Relating neocortical pathology to disability progression in multiple sclerosis using MRI

https://doi.org/10.1016/j.neuroimage.2004.07.046Get rights and content

Cortical grey matter (cGM) develops a substantial burden of pathology in multiple sclerosis (MS). Previous cross-sectional studies have suggested a relationship between measures of cortical atrophy and disability. Our objective was to develop a method for automatically measuring the apparent cGM thickness as well as the integrity of the interface between cGM and subcortical white matter (GM/WM) both globally and regionally on T1-weighted MRI, and use this method in a longitudinal investigation of how these measures differed between patients with stable MS and patients with progressing disability. Measurements were made over the whole brain and for anatomically specified cortical regions, both cross-sectionally at baseline and longitudinally on two MRI scans performed on average 1 year apart. We found a higher average rate of apparent loss of cGM thickness across the whole brain in the group that progressed over the interscan interval compared to the group that remained stable (progressing = −3.13 ± 2.88%/year, stable = 0.06 ± 2.31%/year, P = 0.002). This difference was detected with regional measures in parietal and precentral cortex. In contrast, change in the GM/WM interface integrity did not show detectable regional differences, although the group of MS patients whose disability progressed showed a significant decrease in GM/WM interface integrity compared to the stable group (P = 0.003). Regional measures of apparent loss of cGM thickness enhance sensitivity to cortical pathological changes. A measure of integrity offers a new index of disease-associated cortical changes at the GM/WM interface. The results suggest that progression of disability in MS is associated with the progression of MRI-detectable cortical pathology.

Introduction

MR imaging and histopathology have both shown that the cortical grey matter (cGM) develops a substantial burden of pathology in patients with multiple sclerosis (MS). Postmortem histopathology of the brains of MS patients over a large range of disease duration shows lesions in the cGM (Brownell and Hughes, 1962, Kidd et al., 1999, Lumsden, 1970, Peterson et al., 2001). Proton MR spectroscopy has shown that the concentration of N-acetyl-aspartate (NAA), a biomarker of neuronal integrity, is low in the cGM of patients with early MS (Chard et al., 2002, Kapeller et al., 2001) and secondary-progressive MS (DiMaio et al., 2003). Conventional MRI is insensitive to cortical lesions per se, but image processing approaches confirm the presence of cortical pathology. For example, hypointensity on T2-weighted images in Rolandic cortex has been noted and suggested to be related to pathological iron deposition (Bakshi et al., 2000). A cross-sectional study of T1-weighted MRI scans from early MS patients found lower cGM volume compared to healthy controls (De Stefano et al., 2003). Using high-resolution MRI, a cross-sectional study found reduced thickness globally in MS patients compared to healthy controls, as well as regional decreases in frontal and temporal regions, even in patients with early stage MS (Sailer et al., 2003). In later disease stages, focal loss of cortical thickness was also observed the precentral region (Sailer et al., 2003).

In this paper, we investigated how global and regional measures of cGM pathology in MS differed between MS patients with a stable disease course compared to patients with a progressive disease course. To do this, we characterized the cGM with two measures derived from conventional T1-weighted MRI. The first is a novel method to automatically measure the apparent cGM thickness. The second is a measure related to the integrity of the interface between the cortical grey and subcortical white matter (GM/WM) to quantify pathology affecting this interface. These measures were performed globally and within specified cortical regions both cross-sectionally at baseline and longitudinally. For each subject, we used MRI obtained at two time points on average 1 year apart, as a measurable amount of global atrophy can occur over this time interval, and compared patients who were stable over the interscan interval to patients who worsened over the interscan interval.

Section snippets

Patients

Patients were selected from the Multiple Sclerosis Clinic of the Montreal Neurological Hospital. All met the following criteria: (1) clinically definite MS with a RR or SP course; (2) expanded disability status scale (Kurtzke, 1983) EDSS ≤ 5; (3) at least 1-month interval between the scan and the last exacerbation; and (4) availability of two MRI scans with identical acquisition parameters performed approximately 1 year apart. To investigate changes on MRI during disability progression, we

Results

The subject demographics are shown in Table 1. The groups do not significantly differ from each other on any baseline characteristic.

Discussion

The objective of this work was to investigate how automatically obtained global and regional characteristics of cGM relate to disease course in MS. This allowed us to test directly whether patients that progress in disability also progress with respect to MRI-visible cortical pathology. By investigating whether cross-sectional variables were significantly different between the groups at baseline, the possibility that progression could be predicted was tested as well.

Summary

Detecting cortical pathology on MRI in MS is difficult. Here we have presented an alternative strategy by which the evolution of pathology can be inferred from clinically practical scanning using an image processing methodology that does not require user intervention and is sensitive to changes at a subvoxel resolution. We have applied this to the important problem of distinguishing pathological characteristics associated with disability progression. In previous studies, we have shown that

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