¹¹C-PiB and¹²⁴I-Antibody PET Provide Differing Estimates of Brain Amyloid-β After Therapeutic Intervention

Abstract

PET imaging of amyloid-b (Ab) has become an important component of Alzheimer disease diagnosis. 11 C-Pittsburgh compound B ( 11 C-PiB) and analogs bind to fibrillar Ab. However, levels of nonfibrillar, soluble, aggregates of Ab appear more dynamic during disease progression and more affected by Ab-reducing treatments. The aim of this study was to compare an antibody-based PET ligand targeting nonfibrillar Ab with 11 C-PiB after b-secretase (BACE-1) inhibition in 2 Alzheimer disease mouse models at an advanced stage of Ab 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 11 C-PiB to measure Ab plaque load followed by a scan with the bispecific radioligand 124 I-RmAb158-scFv8D3 to investigate nonfibrillar aggregates of Ab. 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 11 C-PiB-PET and 125 I-RmAb158-scFv8D3 SPECT. Brain tissue was isolated after scanning, and Ab levels were assessed. Results: 124 I-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 125 I-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 Ab aggregates. For both models, mice treated with NB-360 did not display a reduced 11 C-PiB signal compared with untreated controls, and further, both NB-360 and control mice tended, although not reaching significance, to show higher 11 C-PiB signal than the baseline groups. Conclusion: This study demonstrated the ability of an antibody-based radioligand to detect changes in brain Ab levels after anti-Ab therapy in ArcSwe and App NL-G-F mice with pronounced Ab pathology. In contrast, the decreased Ab levels could not be quantified with 11 C-PiB PET, suggesting that these ligands detect different pools of Ab.

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