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Multiple sclerosis features complex pathological changes in gray matter that begin early and eventually lead to diffuse atrophy. Novel approaches to image gray matter microstructural alterations in-vivo are highly sought after and would enable more sensitive monitoring of disease activity and progression. This cross-sectional study aimed to assess the sensitivity of high-gradient diffusion MRI for microstructural tissue damage in cortical and deep gray matter in people with multiple sclerosis and test the hypothesis that reduced cortical cell body density is associated with cortical and deep gray matter volume loss. Forty-one people with multiple sclerosis (ages 24–72, 14 females) and 37 age- and sex-matched healthy controls were scanned on a 3 Tesla Connectom MRI scanner equipped with 300 mT/m gradients using a multi-shell diffusion MRI protocol. The soma and neurite density imaging model was fitted to high-gradient diffusion MRI data to obtain estimates of intra-neurite, intra-cellular, and extra-cellular signal fractions and apparent soma radius. Cortical and deep gray matter microstructural imaging metrics were compared between multiple sclerosis and healthy controls and correlated with gray matter volume, clinical disability and cognitive outcomes. People with multiple sclerosis showed significant cortical and deep gray matter volume loss compared to healthy controls. People with multiple sclerosis showed trends toward lower cortical intra-cellular signal fraction and significantly lower intra-cellular and higher extra-cellular signal fractions in deep gray matter, especially the thalamus and caudate, compared to healthy controls. Changes were most pronounced in progressive disease and correlated with the Expanded Disability Status Scale, but not the Symbol Digit Modalities Test. In multiple sclerosis, normalized thalamic volume was associated with thalamic microstructural imaging metrics. Whereas thalamic volume loss did not correlate with cortical volume loss, cortical microstructural imaging metrics were significantly associated with thalamic volume, and not with cortical volume. Compared to the short diffusion time (Δ=19 ms) achievable on the Connectom scanner, at the longer diffusion time of Δ=49 ms attainable on clinical scanners, multiple sclerosis-related changes in imaging metrics were generally less apparent with lower effect sizes in cortical and deep gray matter. Soma and neurite density imaging metrics obtained from high-gradient diffusion MRI data provide detailed gray matter characterization beyond cortical and thalamic volumes and distinguish multiple sclerosis-related microstructural pathology from healthy controls. Cortical cell body density correlates with thalamic volume, appears sensitive to the microstructural substrate of neurodegeneration and reflects disability status in people with multiple sclerosis, becoming more pronounced as disability worsens.

In multiple sclerosis, individual lesion-type patterns on magnetic resonance imaging might be valuable for predicting clinical outcome and monitoring treatment effects. Neuropathological and imaging studies consistently show that cortical lesions contribute to disease progression. The presence of chronic active white matter lesions harbouring a paramagnetic rim on susceptibility-weighted magnetic resonance imaging has also been associated with an aggressive form of multiple sclerosis. It is, however, still uncertain how these two types of lesions relate to each other, or which one plays a greater role in disability progression. In this prospective, longitudinal study in 100 multiple sclerosis patients (74 relapsing-remitting, 26 secondary progressive), we used ultra-high field 7-T susceptibility imaging to characterize cortical and rim lesion presence and evolution. Clinical evaluations were obtained over a mean period of 3.2 years in 71 patients, 46 of which had a follow-up magnetic resonance imaging. At baseline, cortical and rim lesions were identified in 96% and 63% of patients, respectively. Rim lesion prevalence was similar across disease stages. Patients with rim lesions had higher cortical and overall white matter lesion load than subjects without rim lesions (P = 0.018–0.05). Altogether, cortical lesions increased by both count and volume (P = 0.004) over time, while rim lesions expanded their volume (P = 0.023) whilst lacking new rim lesions; rimless white matter lesions increased their count but decreased their volume (P = 0.016). We used a modern machine learning algorithm based on extreme gradient boosting techniques to assess the cumulative power as well as the individual importance of cortical and rim lesion types in predicting disease stage and disability progression, alongside with more traditional imaging markers. The most influential imaging features that discriminated between multiple sclerosis stages (area under the curve±standard deviation = 0.82 ± 0.08) included, as expected, the normalized white matter and thalamic volume, white matter lesion volume, but also leukocortical lesion volume. Subarachnoid cerebrospinal fluid and leukocortical lesion volumes, along with rim lesion volume were the most important predictors of Expanded Disability Status Scale progression (area under the curve±standard deviation = 0.69 ± 0.12). Taken together, these results indicate that while cortical lesions are extremely frequent in multiple sclerosis, rim lesion development occurs only in a subset of patients. Both, however, persist over time and relate to disease progression. Their combined assessment is needed to improve the ability of identifying multiple sclerosis patients at risk of progressing disease., The study by Treaba et al. investigates the contribution of cortical and susceptibility rim lesions at 7-T on disease burden and progression in multiple sclerosis using modern machine learning algorithms. While longitudinal lesion accumulation predominates for the cortical over the rim lesion type, both types are associated with disability progression., Graphical Abstract Graphical Abstract