Moving Toward Multicenter Therapeutic Trials in Amyotrophic Lateral Sclerosis: Feasibility of Data Pooling Using Different Translocator Protein PET Radioligands

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 (¹¹C-PBR28 and ¹⁸F-DPA714) is feasible, after validation of an established ¹¹C-PBR28 PET pseudo reference analysis technique for ¹⁸F-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 ¹⁸F-DPA714 (Leuven, Belgium) or ¹¹C-PBR28 (Boston, Massachusetts) PET/MRI. For ¹⁸F-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 ¹¹C-PBR28, SUVR images from 60 to 90 min after injection using the WB without ventricles were calculated. Results: In line with previous studies, increased ¹⁸F-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%). ¹⁸F-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 ¹¹C-PBR28 SUVR calculated using the WB without ventricles. Analysis of the ¹⁸F-DPA714 and ¹¹C-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 ¹¹C-PBR28 PET can be extended toward ¹⁸F-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.

Keywords: 11C-PBR28; 18F-DPA714; amyotrophic lateral sclerosis; multicenter; translocator protein.

FIGURE 1.

Surface-based analysis for ¹⁸F-DPA714 in ALS group compared with HV group on SUVR_40–60 with 0.5 projection factor and 6-mm gaussian smoothing was performed using cerebellum, occipital cortex, and WB without ventricles (WB-ventricles) as pseudo reference regions.

FIGURE 2.

Correlations for ¹⁸F-DPA714 between V_T and SUVR_40–60 of left and right primary motor cortices over occipital, cerebellum, and WB without ventricles (WB-ventricles). Blue is non-PVC data; red is after PVC. Solid lines are fitted lines, and dashed line is identity line. Subjects in black circles are low-affinity binders.

FIGURE 3.

Surface-based analysis between participants with ALS and HVs for ¹⁸F-DPA714 SUVR_40–60, ¹¹C-PBR28 SUVR_60–90, and both tracers (¹⁸F-DPA714 SUVR_40–60 combined with ¹¹C-PBR28 SUVR_60–90) using WB without ventricles as pseudo reference region.