Subcortical microglial inflammation is uniquely linked to subpial cortical demyelination in multiple sclerosis

• Subcortical inflammation in MS patients was linked to subpial demyelination. • Cortical demyelination was measured with 7 Tesla Magnetization Transfer Saturation. • Subcortical microglial activation was measured with [11C]PBR28 TSPO PET imaging. • Patients were classified by Principal Component Analysis of subcortical TSPO PET. • Patients with subcortical inflammation had increased disability and cortical atrophy. In multiple sclerosis (MS), pathology of both the subpial cortex and subependymal parenchyma has been strongly linked to compartmentalized meningeal inflammation. The topographical distribution of subpial demyelination can be appraised in vivo using surface-based mapping of magnetization transfer saturation (MTsat) in the cortex with 7T MRI. We combined 7T cortical MTsat mapping with [ 11 C]PBR28 PET molecular imaging of microglia to study the potential influence of subcortical microglial inflammation on cortical pathology. Thirty-eight MS patients (median EDSS: 4.0) and 21 healthy controls (HCs) underwent high resolution 7T MRI and [ 11 C]PBR28 PET. Principal component analysis of [ 11 C]PBR28 PET data was used to phenotype patients as having high (MSHigh) or low (MSLow) subcortical inflammation. Quantitative, surface-based measures of cortical myelin were obtained by sampling MTsat maps at 25%-50%-75% depths from the pia. MSHigh patients presented substantially greater, diffuse reductions in MTsat at all three cortical depths relative to HCs ( P < 0.05). Areas of significantly reduced MTsat were greatest at 25% depth in the frontal, parietal and cingulate cortices, occupying nearly 70% of total cortical area and providing evidence of extensive subpial demyelination. Importantly, MSHigh patients presented increased microstructural abnormalities in subcortical regions ( P < 0.05), alongside higher Expanded Disability Status Score (EDSS) ( P = 0.02), increased odds of progressive MS (odds ratio = 4.85:1 [1.20, 23.26], P = 0.03) and significant cortical atrophy ( P = 0.009). We provide in vivo evidence of a relationship between subcortical microglial inflammation and subpial demyelination in MS that is associated with increased clinical disability.