Association of Cortical Lesion Burden on 7-T Magnetic Resonance Imaging With Cognition and Disability in Multiple Sclerosis

Abstract

Importance: Cortical lesions (CLs) contribute to physical and cognitive disability in multiple sclerosis (MS). Accurate methods for visualization of CLs are necessary for future clinical studies and therapeutic trials in MS.

Objective: To evaluate the clinical relevance of measures of CL burden derived from high-field magnetic resonance imaging (MRI) in MS.

Design, setting, and participants: An observational clinical imaging study was conducted at an academic MS center. Participants included 36 individuals with MS (30 relapsing-remitting, 6 secondary or primary progressive) and 15 healthy individuals serving as controls. The study was conducted from March 10, 2010, to November 23, 2012, and analysis was performed from June 1, 2011, to September 30, 2014. Seven-Tesla MRI of the brain was performed with 0.5-mm isotropic resolution magnetization-prepared rapid acquisition gradient echo (MPRAGE) and whole-brain, 3-dimensional, 1.0-mm isotropic resolution magnetization-prepared, fluid-attenuated inversion recovery (MPFLAIR). Cortical lesions, seen as hypointensities on MPRAGE, were manually segmented. Lesions were classified as leukocortical, intracortical, or subpial. Images were segmented using the Lesion-TOADS (Topology-Preserving Anatomical Segmentation) algorithm, and brain structure volumes and white matter (WM) lesion volume were reported. Volumes were normalized to intracranial volume.

Main outcomes and measures: Physical disability was measured by the Expanded Disability Status Scale (EDSS). Cognitive disability was measured with the Minimal Assessment of Cognitive Function in MS battery.

Results: Cortical lesions were noted in 35 of 36 participants (97%), with a median of 16 lesions per participant (range, 0-99). Leukocortical lesion volume correlated with WM lesion volume (ρ = 0.50; P = .003) but not with cortical volume; subpial lesion volume inversely correlated with cortical volume (ρ = -0.36; P = .04) but not with WM lesion volume. Total CL count and volume, measured as median (range), were significantly increased in participants with EDSS scores of 5.0 or more vs those with scores less than 5.0 (count: 29 [11-99] vs 13 [0-51]; volume: 2.81 × 10-4 [1.30 × 10-4 to 7.90 × 10-4] vs 1.50 × 10-4 [0 to 1.01 × 10-3]) and in cognitively impaired vs unimpaired individuals (count: 21 [0-99] vs 13 [1-54]; volume: 3.51 × 10-4 [0 to 1.01 × 10-4] vs 1.19 × 10-4 [0 to 7.17 × 10-4]). Cortical lesion volume correlated with EDSS scores more robustly than did WM lesion volume (ρ = 0.59 vs 0.36). Increasing log[CL volume] conferred a 3-fold increase in the odds of cognitive impairment (odds ratio [OR], 3.36; 95% CI, 1.07-10.59; P = .04) after adjustment for age and sex and a 14-fold increase in odds after adjustment for WM lesion volume and atrophy (OR, 14.26; 95% CI, 1.06-192.37; P = .045). Leukocortical lesions had the greatest effect on cognition (OR for log [leukocortical lesion volume], 9.65; 95% CI, 1.70-54.59, P = .01).

Conclusions and relevance: This study provides in vivo evidence that CLs are associated with cognitive and physical disability in MS and that leukocortical and subpial lesion subtypes have differing clinical relevance. Quantitative assessments of CL burden on high-field MRI may further our understanding of the development of disability and progression in MS and lead to more effective treatments.

Figures

Figure 1. Identification and Classification of Cortical Lesions on 7-T Magnetic Resonance Imaging

Sample images from the imaging protocol used in the present study. A and B, Coregistered image sections from magnetization-prepared, fluid-attenuated inversion recovery (MPFLAIR) and magnetization-prepared rapid acquisition of gradient echoes (MPRAGE) obtained from a participant with multiple sclerosis. The yellow boxes show an area of higher magnification, which is centered on an anterior frontal lobe leukocortical lesion seen on both MPFLAIR and MPRAGE. C, Samples of lesion subtype classification. Lesions are identified by yellow arrowheads. The top row shows lesions on MPRAGE and the bottom row shows the same lesion on MPFLAIR. Three lesion subtypes were identified: leukocortical (traversing white and gray matter), intracortical (located exclusively within cortex), and subpial (more widespread areas of cortical signal abnormality, arising at the subpial surface, usually in deep sulci and/or traversing multiple sulci or gyri).

Figure 2. Correlation of Leukocortical (LC) and Subpial (SP) Cortical Lesions With Cortical Gray Matter (GM) Volume and White Matter (WM) Lesion Volume

Correlations were tested using Spearman rank correlation testing, with ρ values (magnitude of correlation) and P values shown. The diagonal lines indicate line of best fit through data points. Volumes are normalized to intracranial volume, and are thus unitless.