Positron Emission Tomography with [18F]‐DPA‐714 Unveils a Smoldering Component in Most Multiple Sclerosis Lesions which Drives Disease Progression

Objective To determine the prognostic value of persisting neuroinflammation in multiple sclerosis (MS) lesions, we developed a 18 kDa‐translocator‐protein‐positron emission tomography (PET) ‐based classification of each lesion according to innate immune cell content and localization. We assessed the respective predictive value of lesion phenotype and diffuse inflammation on atrophy and disability progression over 2 years. Methods Thirty‐six people with MS (disease duration 9 ± 6 years; 12 with relapsing–remitting, 13 with secondary‐progressive, and 11 with primary‐progressive) and 19 healthy controls (HCs) underwent a dynamic [18F]‐DPA‐714‐PET. At baseline and after 2 years, the patients also underwent a magnetic resonance imaging (MRI) and neurological examination. Based on a threshold of significant inflammation defined by a comparison of [18F]‐DPA‐714 binding between patients with MS and HCs, white matter lesions were classified as homogeneously active (active center), rim‐active (inactive center and active periphery), or nonactive. Longitudinal cortical atrophy was measured using Jacobian integration. Results Patients with MS had higher innate inflammation in normal‐appearing white matter (NAWM) and cortex than HCs (respective standardized effect size = 1.15, 0.89, p = 0.003 and