The effects of Natalizumab Treatment on Astrocyte Metabolism in Multiple Sclerosis: A Longitudinal 11C-acetate PET study

Objective Astrocyte activation is increasingly recognized as an important component of multiple sclerosis (MS) pathology. Natalizumab (NTZ), a highly effective therapy for relapsing-remitting MS (RRMS), primarily blocks leukocyte trafficking into the central nervous system. However, its effects on astrocytic metabolism remain unclear. We investigated astrocyte-associated metabolic changes after NTZ treatment using quantitative 1-11C-acetate positron emission tomography (PET). Methods Seven patients with RRMS underwent quantitative 1-11C-acetate PET before and after NTZ treatment. PET-derived k2, an index of oxidative acetate metabolism, was analyzed voxel-wise and within GM and white-matter volumes of interest. Clinical status and brain magnetic resonance imaging (MRI) findings were assessed, and cognitive performance was evaluated using Rao's Brief Repeatable Battery of Neuropsychological Tests. Results After NTZ treatment, k2 decreased in all patients compared with pretreatment levels. Both gray and white matter showed significant reductions, and voxel-based analysis demonstrated widespread decreases across cortical and subcortical regions of the cerebrum and cerebellum, with no regions showing significant posttreatment increases. MRI showed no worsening; Expanded Disability Status Scale scores were stable or improved, and cognitive performance was generally stable, with improvements in selected subtests. Interpretation Quantitative 1-11C-acetate PET demonstrated a whole-brain reduction in astrocyte-associated metabolism after NTZ treatment in RRMS, most prominently in gray matter. NTZ may modulate astrocyte activity, in addition to its established effects on peripheral immune cell trafficking.