Moving towards multicenter therapeutic trials in ALS: feasibility of data pooling using different TSPO positron emission tomography (PET) radioligands.

RATIONALE: 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, some challenges have to be 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 pseudoreference analysis technique for (18)F-DPA714. Methods: 7 ALS-Belgium (58.9+/-6.7 years,5M) and 8 HV-Belgium (52.1+/-15.2 years,3M); and 7 ALS-US (53.4+/-9.8 years,5M) and 7 HV-US (54.6+/-9.6 years,4M) from a previously published study (1) underwent dynamic (18)F-DPA714 (Leuven, Belgium) or (11)C-PBR28 (Boston, US) PET-MR scans. For (18)F-DPA714, volume of distribution (VT) maps were compared to standardized uptake value ratios (SUVR)40-60 calculated using the pseudoreference regions (1)cerebellum, (2)occipital cortex, and (3)whole brain without ventricles (WB-ventricles). Also for (11)C-PBR28, SUVR60-90 using WB-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, as measured by both VT and SUVR40-60 approaches. Highest sensitivity was found for SUVRWB-ventricles (average cluster 21.6+/-0.1%). (18)F-DPA714 VT ratio and SUVR40-60 results were highly correlated (r>0.8, p<0.001). A similar pattern of increased uptake (average cluster 20.5+/-0.5%) in primary motor cortices was observed in ALS with (11)C-PBR28 using the SUVRWB-ventricles. Analysis of the (18)F-DPA714 and (11)C-PBR28 data together, resulted in a more extensive pattern of significant increased glial activation in the bilateral primary motor cortices. Conclusion: The same pseudoreference region analysis technique for (11)C-PBR28 PET imaging can be extended towards (18)F-DPA714 PET. Therefore, in ALS, standardized analysis across these two tracers enables pooling of TSPO PET data across multiple centers and increase power of TSPO as biomarker for future therapeutic trials.