Moving Toward Multicenter Therapeutic Trials in Amyotrophic Lateral Sclerosis: Feasibility of Data Pooling Using Different Translocator Protein PET Radioligands
Donatienne Van Weehaeghe, Suma Babu, Joke De Vocht, Nicole R. Zürcher, Sheena Chew, Chieh-En Jane Tseng, Marco L. Loggia, Michel Koole, Ahmadreza Rezaei, Georg Schramm, Philip Van Damme, Jacob M. Hooker, Koen Van Laere, Nazem Atassi
Abstract
Neuroinflammation has been implicated in amyotrophic lateral sclerosis (ALS) and can be visualized using translocator protein (TSPO) radioligands. To become a reliable pharmacodynamic biomarker for ALS multicenter trials, TSPO radioligands have some challenges to overcome. We aimed to investigate whether multicenter data pooling of different TSPO tracers ( 11 C-PBR28 and 18 F-DPA714) is feasible, after validation of an established 11 C-PBR28 PET pseudo reference analysis technique for 18 F-DPA714. Methods: Seven ALS patients from Belgium (58.9 6.7 y old, 5 men and 2 women), 8 healthy volunteers from Belgium (52.1 15.2 y old, 3 men and 5 women), 7 ALS patients from the United States (53.4 9.8 y old, 5 men and 2 women), and 7 healthy volunteers from the United States (54.6 9.6 y old, 4 men and 3 women) from a previously published study underwent dynamic 18 F-DPA714 (Leuven, Belgium) or 11 C-PBR28 (Boston, Massachusetts) PET/MRI. For 18 F-DPA714, maps of total volume of distribution (V T ) were compared with SUV ratio (SUVR) images from 40 to 60 min after injection (SUVR 40-60 ) calculated using the pseudo reference regions cerebellum, occipital cortex, and whole brain (WB) without ventricles. For 11 C-PBR28, SUVR images from 60 to 90 min after injection using the WB without ventricles were calculated. Results: In line with previous studies, increased 18 F-DPA714 uptake (17.0% 5.6%) in primary motor cortices was observed in ALS subjects, as measured by both V T and SUVR 40-60 approaches. The highest sensitivity was found for SUVR calculated using the WB without ventricles (average cluster, 21.6% 0.1%). 18 F-DPA714 V T ratio was highly correlated with the SUVR 40-60 (r . 0.8, P , 0.001). A similar pattern of increased uptake (average cluster, 20.5% 0.5%) in the primary motor cortices was observed in ALS subjects for 11 C-PBR28 SUVR calculated using the WB without ventricles. Analysis of the 18 F-DPA714 and 11 C-PBR28 data together resulted in a more extensive pattern of significantly increased glial activation bilaterally in the primary motor cortices. Conclusion: The same pseudo reference region analysis technique for 11 C-PBR28 PET can be extended toward 18 F-DPA714 PET. Therefore, in ALS, standardized analysis across these 2 tracers enables pooling of TSPO PET data across multiple centers and increases the power of TSPO as a biomarker for future therapeutic trials.