11C-PiB and 124I-Antibody PET Provide Differing Estimates of Brain Amyloid-β After Therapeutic Intervention

Abstract

PET imaging of amyloid-β (Aβ) has become an important component of Alzheimer disease 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 2 Alzheimer disease mouse models at an advanced stage of Aβ pathology. Methods: Transgenic ArcSwe mice (16 mo old) were treated with the BACE-1 inhibitor NB-360 for 2 mo, whereas another group was kept as controls. A third group was analyzed at the age of 16 mo as a 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 to another mouse model, App^NL-G-F In this case, NB-360 treatment was initiated at the age of 8 mo and animals were scanned with ¹¹C-PiB-PET and ¹²⁵I-RmAb158-scFv8D3 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 App^NL-G-F mice. Radioligand in vivo concentrations corresponded to 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 with 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 App^NL-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 Aβ.

Keywords: 11C-PiB; Alzheimer disease; BACE-1 inhibition; amyloid-β; antibody-based PET.