In vivo detection of connectivity between cortical and white matter lesions in early MS

Background: The relationship between cortical lesions (CLs) and white matter lesions (WMLs) in multiple sclerosis (MS) is poorly understood. Pathological studies support a topographical association between CLs and underlying subcortical WMLs and suggest CLs may play a role in both disease initiation and progression. We hypothesized that cortical MS lesions are physically connected to white matter MS lesions via axonal connections. Objective: To assess the presence of CL-WML connectivity utilizing novel magnetic resonance imaging (MRI) methodology. Methods: In all, 28 relapsing-remitting MS patients and 25 controls received 3T MRI scans, including double inversion recovery (DIR) for CL detection coupled with diffusion tensor imaging (DTI). CL and WML maps were created, and DTI was used to calculate inter-lesional connectivity and volumetric connectivity indices. Results: All patients showed inter-lesional WML connectivity (median 76% of WMLs connected to another WML; interquartile range (IQR), 58%-88%). On average, 52% of detected CLs per patient were connected to at least one WML (IQR, 42%-71%). Volumetric connectivity analysis showed significantly elevated cortical lesion ratios in MS patients (median, 2.3; IQR, 1.6-3.3) compared to null MS and healthy control datasets (p<0.001). Conclusion: These findings provide strong evidence of inter-lesional connectivity between CLs and WMLs, supporting our hypothesis of intrinsic CL-WML connectivity.