The association between intra- and juxta-cortical pathology and cognitive impairment in multiple sclerosis by quantitative T2* mapping at 7 T MRI

Abstract

Using quantitative T₂* at 7 Tesla (T) magnetic resonance imaging, we investigated whether impairment in selective cognitive functions in multiple sclerosis (MS) can be explained by pathology in specific areas and/or layers of the cortex. Thirty-one MS patients underwent neuropsychological evaluation, acquisition of 7 T multi-echo T₂* gradient-echo sequences, and 3 T anatomical images for cortical surfaces reconstruction. Seventeen age-matched healthy subjects served as controls. Cortical T₂* maps were sampled at various depths throughout the cortex and juxtacortex. Relation between T₂*, neuropsychological scores and a cognitive index (CI), calculated from a principal component analysis on the whole battery, was tested by a general linear model. Cognitive impairment correlated with T₂* increase, independently from white matter lesions and cortical thickness, in cortical areas highly relevant for cognition belonging to the default-mode network (p < 0.05 corrected). Dysfunction in different cognitive functions correlated with longer T₂* in selective cortical regions, most of which showed longer T₂* relative to controls. For most tests, this association was strongest in deeper cortical layers. Executive dysfunction, however, was mainly related with pathology in juxtameningeal cortex. T₂* explained up to 20% of the variance of the CI, independently of conventional imaging metrics (adjusted-R²: 52-67%, p < 5.10^{- 4}). Location of pathology across the cortical width and mantle showed selective correlation with impairment in differing cognitive domains. These findings may guide studies at lower field strength designed to develop surrogate markers of cognitive impairment in MS.

Keywords: 7 Tesla MRI; BVMT - DR, brief visuo-spatial memory test delayed recall; BVMT, brief visual memory test; CI, cognitive index; CVLT, California verbal learning test; Cognitive impairment; DB, digit span backward; DF, digit span forward; DR, delayed recall; EDSS, expanded disability status score; JLOT, judgment of line orientation test; LDCR, long delayed cued recall; LDFR, long delayed free recall; Laminar cortical pathology; MRI, magnetic resonance imaging; MS, multiple sclerosis; Multiple sclerosis; NP, neuropsychological; PCA, principal component analysis; SDMT, symbol digit modalities test; T2*; TMT, trail making test; TOT, total recall; WCST, Wisconsin card sorting test; WM, white matter; WMLV, white matter lesion volume; q-T2*, quantitative T2*.

Fig. 1

Areas of correlation between cortical quantitative T₂* and cognitive index in multiple sclerosis. Overlay of the general linear model (GLM) significance maps (p < 0.05 corrected for multiple comparisons) showing clusters with a positive (red yellow) or negative (blue) correlation between q-T₂* at 25%, 50%, and 75% depth from the pial surface and cognitive impairment as measured by the cognitive index (CI) in MS subjects. A) Covariates of no interest included in the model were age, gender, education and cortical thickness at the vertex level. B) Covariates of no interest included in the model were age, gender, education, cortical thickness at the vertex level and white matter lesion volume. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Cortical areas showing a significant correlation between quantitative T₂* at 7 Tesla and neuropsychological performance at different cognitive domains in subjects with multiple sclerosis. Overlay of the general linear model (GLM) significance maps (p < 0.05 corrected for multiple comparisons) showing clusters with a correlation between q-T₂* at 25%, 50%, and 75% depth from the pial surface and neuropsychological tests' scores. A negative correlation was found between cortical q-T₂*, SDMT, CVLT LDFR scores (lower performance reflected in lower raw scores). A positive correlation was found between cortical q-T₂* and WCST ERR (lower performance reflected in higher raw scores). Age, gender, education, WM lesion volume and cortical thickness at the vertex level were included as covariates of no interest in the model. SDMT: symbol digit modalities test; CVLT LDFR: California verbal learning test long delayed free recall; WCST ERR: Wisconsin card sorting test total errors; WM: white matter; q-T₂*: quantitative T₂*.

Fig. 3

Total surface area of clusters exhibiting a significant correlation between intra- or juxta-cortical quantitative T₂* and cognitive results. Top panel: total surface area of clusters from general linear model (GLM) analyses including age, gender, education and cortical thickness as covariates of no interest. Bottom panel: total surface of clusters from GLM analyses including age, gender, education, cortical thickness and white matter lesion volume as covariates of no interest. Dashed vertical lines represent the surface between cortex and white matter. CI: cognitive index; SDMT: symbol digit modalities test; CVLT LDFR: California verbal learning test long delayed free recall; BVMT - DR: brief visuospatial memory test delayed recall; JLOT: judgment of line orientation test; TMT: trail making test; WCST ERR: Wisconsin card sorting test total errors; WCST PERS: Wisconsin card sorting test total perseverations.

Fig. 4

Adjusted variable plots of partial correlation between cognitive index (CI) and cortical quantitative T₂* at 50% depth from the pial surface in clusters from general linear model (GLM) exhibiting a statistical significance (p < 0.0001). Covariates of no interest included in the model were age, gender, education, cortical thickness and white matter lesion volume. For each cluster are displayed: 1) the partial correlation coefficient (r_p) between CI residual and mean T₂* residual; 2) the percentage of CI variance explained by T₂* (%Expl.var) in addition to the other predictors. Location of clusters: 1. inferior parietal; 2. superior parietal; 3. precuneus; 4. precuneus; 5. precentral; 6. superior frontal; 7. cuneus; 8. superior parietal.