The association between intra- and juxta-cortical pathology and cognitive impairment in multiple sclerosis by quantitative T 2 * 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.

Spatial Correlation of Pathology and Perfusion Changes within the Cortex and White Matter in Multiple Sclerosis

“…The near universally stronger cGM and NAWM perfusion association and deteriorating perfusion metrics with disease progression also confirmed in prior studies 12,14,16, 26, 27 suggests that perfusion is sensitive to a common pathophysiological mechanism reflecting concomitant but not necessarily co-dependent cGM and WM pathology in MS. Findings are supported by a recently reported DTI study 8 suggesting that perfusion could serve as a useful surrogate of disease activity in addition to routine structural imaging.…”

“…This assertion is supported by various pathological and imaging studies 8, 22–24 which have shown that cGM lesions may develop prior to the appearance of WM plaques 22 , arise independently of, and are poorly correlated with T2h-l formation 23,24 . A number of pathological and imaging papers have increasingly implicated an independent etiology for cGM lesion formation attributed either to the direct presence of meningeal-derived neurotoxic substances or secondary microglial activation mediated through meningeal/supbial inflammation and manifest as a gradient of demyelination centered upon the subpial cortex 24, 27 .…”

“…A recent correlative study of quantitative cortical T2* at 7T and 3T-derived surface and tract based analysis found a correlation between WM tract DTI and cGM integrity although this was not spatially specific, reflecting a common sensitivity to MS pathological changes 8 . Steenwijk et al 9 used DTI at 3T to investigate the association between regional GM atrophy and pathology in anatomically connected WM tracts in RRMS, SPMS and primary-progressive MS patients demonstrating a relationship between NAWM tract FA and deep GM and cGM.…”

“…Although some studies suggest a relationship between normal appearing WM (NAWM) atrophy and cGM damage 4, 5 , others suggest that cGM disease progression is either independent from or only partly related to WM abnormalities 6, 7 . Louapre et al, utilizing DTI at 7T, found a lack of spatial specificity between NAWM tracts and the overlying cGM 8 . Steenwijk et al 9 reported a stronger relationship between cGM atrophy and WM tract pathology in RRMS compared to SPMS patients, concluding that the association between NAWM and cGM becomes increasingly independent with disease progression.…”

Higher Cortical Dysfunction Resembling Corticobasal Syndrome in 2 Patients with Multiple Sclerosis

“…Recent pathologic studies indicate that there is involvement of gray matter structures as well. Gray matter atrophy and lesions can occur early in the disease and may correlate with degeneration, not just demyelination [10]. A consensus panel determined that brain volume is a valuable measure and should be included in the determination of whether or not there is evidence of disease activity at follow up visits [11].…”