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

• Published in: Journal of Nuclear Medicine Vol. 61; no. 11; pp. 1621 - 1627
• Main Authors: Van Weehaeghe, Donatienne, Babu, Suma, De Vocht, Joke, Zürcher, Nicole R., Chew, Sheena, Tseng, Chieh-En J., Loggia, Marco L., Koole, Michel, Rezaei, Ahmadreza, Schramm, Georg, Van Damme, Philip, Hooker, Jacob M., Van Laere, Koen, Atassi, Nazem
• Format: Journal Article
• Language: English
• Published: United States Society of Nuclear Medicine 01.11.2020
• Subjects: Acetamides - pharmacokinetics; Adult; Aged; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - diagnostic imaging; Amyotrophic Lateral Sclerosis - drug therapy; Biomarkers; Carbon Radioisotopes - pharmacokinetics; Cerebellum; Clinical trials; Clinical Trials as Topic; Clusters; Feasibility; Feasibility Studies; Female; Fluorine isotopes; Fluorine Radioisotopes - pharmacokinetics; Humans; Inflammation; Injection; Magnetic resonance imaging; Male; Mathematical analysis; Medical imaging; Middle Aged; Neurology; Occipital lobe; Pharmacodynamics; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Proteins; Pyrazoles - pharmacokinetics; Pyridines - pharmacokinetics; Pyrimidines - pharmacokinetics; Radioisotopes; Receptors, GABA - metabolism; Tomography; Tracers; Belgium; United States > US; 11C-PBR28; 18F-DPA714; translocator protein; amyotrophic lateral sclerosis; multicenter
• ISSN: 0161-5505; 1535-5667; 2159-662X; 2159-662X; 1535-5667
• DOI: 10.2967/jnumed.119.241059

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 ( C-PBR28 and F-DPA714) is feasible, after validation of an established C-PBR28 PET pseudo reference analysis technique for F-DPA714. 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 F-DPA714 (Leuven, Belgium) or C-PBR28 (Boston, Massachusetts) PET/MRI. For F-DPA714, maps of total volume of distribution (V ) were compared with SUV ratio (SUVR) images from 40 to 60 min after injection (SUVR ) calculated using the pseudo reference regions cerebellum, occipital cortex, and whole brain (WB) without ventricles. For C-PBR28, SUVR images from 60 to 90 min after injection using the WB without ventricles were calculated. In line with previous studies, increased F-DPA714 uptake (17.0% ± 5.6%) in primary motor cortices was observed in ALS subjects, as measured by both V and SUVR approaches. The highest sensitivity was found for SUVR calculated using the WB without ventricles (average cluster, 21.6% ± 0.1%). F-DPA714 V ratio was highly correlated with the SUVR ( > 0.8, < 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 C-PBR28 SUVR calculated using the WB without ventricles. Analysis of the F-DPA714 and C-PBR28 data together resulted in a more extensive pattern of significantly increased glial activation bilaterally in the primary motor cortices. The same pseudo reference region analysis technique for C-PBR28 PET can be extended toward 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.