Objective:

The objectives of this study are to determine the ability of [F-18]PBR06-PET to predict progression independent of disease activity (PIRA) in multiple sclerosis (MS) and compare it with clinical measures, MRI volumetrics, and serum biomarkers .

Background:

Microglial-activation may play a role in disease progression in MS. [F-18]PBR06-PET targeting 18-kDa-translocator-protein (TSPO) can detect abnormal microglial activation (MA) in MS.

Design/Methods:

Twenty-two MS patients (mean age, 46±13 years; 16 females) who underwent [F-18]PBR06-PET scans were prospectively followed-up for an average duration of 4.5-years. PIRA was defined as at-least 0.5- and 1.0-point increase in EDSS in subjects with EDSS>/=5 and <5, respectively, without associated clinical-relapse or MRI-activity. Logarithmically transformed “glial activity load on PET” scores (calculated as the sum of voxel-by-voxel z-scores ≥4), “lnGALP,” were compared between progressors (PIRA) versus non-progressors (NP), and compared with differences in clinical measures, serum biomarkers, and total cortical thickness (CoT) between groups. Multivariate regression and receiver-operating-characteristic (ROC) analyses were performed.

Results:

Cortical gray-matter (CoGM) lnGALP was higher and CoT was lower in PIRA versus NP (11.27±1.1 vs. 9.43±1.38, +19.5%, p = 0.009, and 2.44±0.08 vs. 2.51±0.07, -2.7%, p=0.03). On multivariate regression, CoGM-lnGALP was predictive of PIRA independent of CoT, age, EDSS, fatigue scores, disease-modifying treatment (DMT) and TSPO-binding-status (p<0.05). On ROC analysis, the AUC was 0.854 and 0.75 for PET and CoT, respectively (Youden’s-index (YI) 0.69 and 0.52). A CoGM-lnGALP cut-off value of >9.94 predicted PIRA with 100% sensitivity and 68.7% specificity that improved to 100% sensitivity and 100% specificity in a subgroup of patients treated with high-efficacy DMTs (n=13, YI=1, p<0.001). Serum neurofilament light chain and glial-fibrillary acid protein levels, brain and thalamic volume, and white matter lnGALP were not significantly different between groups.

Conclusions:

Cortical microglial-activation on [F-18]PBR06-PET independently predicts PIRA in MS. Larger, prospective, longitudinal studies of [F-18]PBR06-PET in MS and PIRA are urgently warranted.