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

Abstract

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 AE 6 years; 12 with relapsing-remitting, 13 with secondary-progressive, and 11 with primary-progressive) and 19 healthy controls (HCs) underwent a dynamic [ 18 F]-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 [ 18 F]-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 < 0.001). Out of 1,335 non-gadolinium-enhancing lesions, 53% were classified as homogeneously-active (median = 17 per patient with MS), 6% rim-active (median = 1 per patient with MS), and 41% non-active (median = 14 per patient with MS). The number of homogenously-active lesions was the strongest predictor of longitudinal changes, associating with cortical atrophy (β = 0.49, p = 0.023) and Expanded Disability Status Scale (EDSS) changes (β = 0.35, p = 0.023) over 2 years. NAWM and cortical binding were not associated to volumetric and clinical changes. Interpretation: The [ 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.

Choroid plexuses at the interface of peripheral immunity and tissue repair in multiple sclerosis

“…Supporting this hypothesis, their enlargement was shown to predict the slow expansion of chronic active periventricular lesions on MRI [56 ▪▪ ]. On TSPO-PET, a similar correlation was found between ChP enlargement and the percentage of chronic MS lesions containing a smoldering inflammatory component, the strength of the association being higher in periventricular white matter [57 ▪ ]. Finally, our group recently reported that greater ChP size was associated with lower periventricular remyelination ( r = −0.79, P = 0.0018) in two independent cohorts of PwMS [55 ▪ ].…”

Expression of Bruton´s tyrosine kinase in different type of brain lesions of multiple sclerosis patients and during experimental demyelination

“…Beside targeting both adaptive and innate peripheral immune responses, the CNS penetrance and effect on both B cells and microglia/macrophages suggest that BTKi can be an attractive approach to treat low-level inflammation in smouldering MS. Activation and functional change of microglia in the normalappearing white matter (NAWM) and in the rim of chronic active lesions participate in propagation of chronic tissue damage and maintaining such low-level chronic inflammation in concert with astrocytes, B and T lymphocytes (20)(21)(22). Microglia activation in the NAWM can be visualized by PET, while chronic active lesions are reflected on MRI as slowly evolving (SEL) and paramagnetic rim lesions (PRLs) (14,(23)(24)(25). Chronic active lesions as PRLs are already present in the early stage of MS and associate with progressive MS and advanced clinical disability (26)(27)(28)(29).…”

Mitochondrial complex I activity in microglia sustains neuroinflammation

“…In multiple sclerosis (MS), chronic active, slowly expanding, smouldering lesions characterized by the accumulation of myeloid cells at the lesion edge are associated with brain atrophy and predict the accumulation of irreversible disability, which in turn drives disease progression 4 – 6 . In these lesions, persistently activated myeloid cells are a continuous source of neurotoxic factors, including tumour necrosis factor (TNF), interleukin-1β (IL-1β), nitric oxide (NO) and reactive oxygen species (ROS), causing remyelination failure and secondary neuronal/axonal damage 7 .…”