Glial Activity Load on PET Reveals Persistent “Smoldering” Inflammation in MS Despite Disease-Modifying Treatment

Abstract

Purpose of the Report 18F-PBR06-PET targeting 18-kDa translocator protein can detect abnormal microglial activation (MA) in multiple sclerosis (MS). The objectives of this study are to develop individualized mapping of MA using 18F-PBR06, to determine the effect of disease-modifying treatment (DMT) efficacy on reducing MA, and to determine its clinical, radiological, and serological correlates in MS patients. Patients and Methods Thirty 18F-PBR06-PET scans were performed in 22 MS patients (mean age, 46 ± 13 years; 16 females) and 8 healthy controls (HCs). Logarithmically transformed “glial activity load on PET” scores (calculated as the sum of voxel-by-voxel z-scores ≥4), “lnGALP,” were compared between MS and HC and between MS subjects on high-efficacy DMTs (H-DMT, n = 13) and those on no or lower-efficacy treatment, and correlated with clinical measures, serum biomarkers, and cortical thickness. Results Cortical gray matter (CoGM) and white matter (WM) lnGALP scores were higher in MS versus HC (+33% and +48%, P < 0.001). In H-DMT group, CoGM and WM lnGALP scores were significantly lower than lower-efficacy treatment (P < 0.01) but remained abnormally higher than in HC group (P = 0.006). Within H-DMT patients, CoGM lnGALP scores correlated positively with physical disability, fatigue and serum glial fibrillary acid protein levels (r = 0.65–0.79, all P's < 0.05), and inversely with cortical thickness (r = −0.66, P < 0.05). Conclusions High-efficacy DMTs decrease, but do not normalize, CoGM and WM MA in MS patients. Such “residual” MA in CoGM is associated with clinical disability, serum biomarkers, and cortical degeneration. Individualized mapping of translocator protein PET using 18F-PBR06 is clinically feasible and can potentially serve as an imaging biomarker for evaluating “smoldering” inflammation in MS patients.