Unraveling cortical pathology in multiple sclerosis using the T1‐/T2‐weighted ratio?

Multiple sclerosis (MS) pathology significantly affects the cortical gray matter from the earliest disease stages. Cortical pathology in MS has been shown to represent a main determinant of physical and cognitive impairment and to predict transition to clinically definite MS and progressive disease. The pathological processes that affect the cortex in MS are heterogeneous and include significant subpial demyelination that involves the juxtameningeal cortical layers, neuroaxonal loss, gliosis, and dendrite abnormalities. Although neuropathological studies have extensively described and characterized cortical demyelination in MS, its in vivo detection remains suboptimal. The main technical obstacles to the development of imaging tools able to detect and monitor in vivo cortical demyelination in the disease are represented by the small dimensions of cortical lesions, the convoluted geometry of the cortex, and the relatively low cortical myelin content compared to the underlying white matter. Despite recent advancements in magnetic resonance (MR) imaging (MRI), noninvasive mapping of myelin in the brain still remains a challenge. None of the currently available contrasts used for assessing cortical demyelination is specific for myelin, given that each can be affected by sequence parameters and by other biological components of the cortex including water content, iron, cells, or fiber density. Novel approaches for noninvasive mapping of myelin distribution patterns in the human cortex rely on integrating multiple MRI contrasts in a multimodal imaging framework to increase sensitivity to cortical myelin content. Among these, the ratio of T1and T2-weighted image intensities (T1w/T2w) from standard MRI protocols has been suggested to enhance the contrast-to-noise ratio for myelin. The method takes advantage of the fact that the T1-weighted signal is positively correlated with myelin and the T2-weighted negatively so, making the ratio of the two weightings more specific to myelin. Previous data in healthy subjects found an excellent agreement between the gradients of the myelin maps and the gradients of published probabilistic cytoarchitectonically defined cortical areas. In this issue of the Annals of Neurology, two research articles show the application of the T1w/T2w ratio to the study of cortical pathology in MS. Nakamura et al investigated, in postmortem in situ scans from six cadavers with MS, whether T1w/T2w ratio measures could detect changes in myelin cortical status, as measured by myelin density on tissue blocks immunostained with the rat anti-PLP (proteolipid protein) antibody. The results showed that the T1w/T2w ratio values significantly differed between demyelinated and myelinated cortex. The investigators also found that the T1w/T2w ratio had a greater effect size in differentiating demyelinated and myelinated cortex than magnetization transfer ratio, a semiquantitative MR contrast used in several imaging studies to assess subtle changes in the biochemical architecture and composition of brain tissue in MS. These findings suggest that the T1w/T2w ratio obtained from standard MRI protocols could be a sensitive marker of cortical demyelination in MS and, potentially, a simple and fast measure well suited for clinical applications, especially compared to quantitative MRI methods that generally require longer acquisition times. Rughart et al applied T1w/T2w cortical mapping in a cohort of 168 subjects with early MS. Relative to healthy controls, MS cases had significantly reduced T1w/ T2w ratio in widespread regions of the cortical ribbon, mainly localized in the occipital cortex and the posterior cingulate gyrus. In patients, T1w/T2w ratio changes occurred in the absence of significant cortical atrophy, and they correlated with performance in verbal memory free recall. Interestingly, the same investigators found that, in ex vivo brain tissue specimens from 9 cases with progressive MS, T1w/T2w ratio measurements in the normalappearing cortical gray matter (NACGM) correlated with dendrite density, but not with myelin content. Overall, these findings suggest that the T1w/T2w ratio, whereas sensitive in detecting cortical pathology in