11C-PIB and 124I-antibody PET provide differing estimates of brain amyloid-beta after therapeutic intervention.

Positron emission tomography (PET) imaging of amyloid-β (Aβ) has become an important component of Alzheimer's disease (AD) diagnosis. 11C-Pittsburgh compound B (11C-PiB) and analogs bind to fibrillar Aβ. However, levels of nonfibrillar, soluble aggregates of Aβ, appear more dynamic during disease progression and more affected by Aβ reducing treatments. The aim of this study was to compare an antibody-based PET ligand, targeting nonfibrillar Aβ, with 11C-PiB after β-secretase (BACE-1) inhibition in two AD mouse models at an advanced stage of Aβ pathology. Methods: Transgenic ArcSwe mice (16 months) were treated with the BACE-1 inhibitor NB-360 for 2 months, while another group was kept as controls. A third group was analyzed at the age of 16 months as baseline. Mice were PET scanned with 11C-PiB to measure Aβ plaque load followed by a scan with the bispecific radioligand 124I-RmAb158-scFv8D3 to investigate nonfibrillar aggregates of Aβ. The same study design was then applied for another mouse model, AppNL-G-F. In this case, NB-360 treatment was initiated at the age of 8 months and animals were scanned with 11C-PiB-PET and 125I-RmAb158-scFv8D3 single-photon emission computer tomography (SPECT). Brain tissue was isolated after scanning and Aβ levels were assessed. Results: 124I-RmAb158-scFv8D3 concentrations measured with PET in hippocampus and thalamus of NB-360 treated ArcSwe mice were similar to those observed in baseline animals and significantly lower than concentrations observed in same-age untreated controls. Reduced 125I-RmAb158-scFv8D3 retention was also observed with SPECT in hippocampus, cortex and cerebellum of NB-360 treated AppNL-G-F mice. Radioligand in vivo concentrations corresponded with postmortem brain tissue analysis of soluble Aβ aggregates. For both models, mice treated with NB-360 did not display a reduced 11C-PiB signal compared to untreated controls, and further, both NB-360 and control mice tended, although not reaching significance, to show higher 11C-PiB signal than the baseline groups. Conclusion: This study demonstrated the ability of an antibody-based radioligand to detect changes in brain Aβ levels after anti-Aβ therapy in ArcSwe and AppNL-G-F mice with pronounced Aβ pathology. In contrast, the decreased Aβ levels could not be quantified with 11C-PiB PET, suggesting that these ligands detect different pools of the Aβ.