LAUSR

OBJECTIVE To determine the prognostic value of persisting neuroinflammation in multiple sclerosis (MS) lesions, we developed a 18kDa-translocator-protein-PET based classification of each lesion according to innate immune cell content and localization, and 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 (PwMS, disease duration 9±6y; 12 relapsing-remitting, 13 secondary -progressive, 11 primary-progressive) and 19 healthy controls (HC) underwent a dynamic [18 F]-DPA-714-PET. At baseline and after 2 years, patients also underwent MRI and neurological examination. Based on a threshold of significant inflammation defined by a comparison of [18 F]-DPA-714 binding between PwMS and HC, white matter lesions were classified as homogeneously-active (active center), rim-active (inactive center and active periphery) or non-active. Longitudinal cortical atrophy was measured using Jacobian integration. RESULTS PwMS had higher innate inflammation in normal appearing white matter (NAWM) and cortex than HC (respective standardized effect size: 1.15, 0.89, p: 0.003 and <0.001). Out of 1335 non-gadolinium-enhancing lesions, 53% were classified homogeneously-active (median:17/PwMS), 6% rim-active (1/PwMS) and 41% non-active (14/PwMS). The number of homogenously-active lesions was the strongest to predict longitudinal changes, associating with cortical atrophy (β =0.49, p=0.023) and Expanded Disability Status Scale changes (β=0.35, p=0.023) over 2 years. NAWM and cortical binding were not associated to volumetric and clinical changes. INTERPRETATION [18 F]-DPA-714-PET revealed that an unexpectedly high proportion of MS lesions have a smoldering component, which predicts atrophy and clinical progression. This suggests that following the acute phase, most lesions develop a chronic inflammatory component, promoting neurodegeneration and clinical progression. This article is protected by copyright. All rights reserved.