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

Silvio R Meier,Stina Syvänen,Ulf Neumann,Takaomi C Saido,Jonas Eriksson,Johanna Rokka,Dag Sehlin,Takashi Saito,Victoria Lim Falk,Sahar Roshanbin

doi:10.2967/jnumed.121.262083

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, AppNL-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 AppNL-G-F mice. Radioligand invivo 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 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 Aβ.

Highlights

Alzheimers disease (AD) is a growing socioeconomic burden on the society and health care that in most countries is characterized by an aging population [1]
ArcSwe and AppNL-G-F mice, treated with BACE-1 inhibitor NB-360 or with vehicle, were Positron emission tomography (PET) scanned with 11C-PiB followed by a 124I-RmAb158-scFv8D3 PET scan or a 125IRmAb158-scFv8D3 single-photon emission computer tomography (SPECT) scan
When quantified as standard uptake value (SUV), a similar trend was observed in hippocampus (Hpc), cortex (Ctx), thalamus (Thl) and cerebellum (Cer), but the difference was not significant and inter-animal variation was large (Fig. 1B). 11C-PiB retention in AppNL-G-F mice was alike in all three groups (Fig. 1C)

Summary

Introduction

Alzheimers disease (AD) is a growing socioeconomic burden on the society and health care that in most countries is characterized by an aging population [1]. In spite of intense research over the last decades, no treatment is available that halts the underlying disease mechanisms and stops the pathological changes in the AD brain. Accumulation of amyloid-beta (Aβ) plaques is the core feature of histopathological diagnosis of AD and can be visualized and quantified by molecular imaging. Positron emission tomography (PET) is today a valuable tool for assessment of brain amyloidosis in vivo. Amyloid imaging with PET has become a regularly used inclusion criterion for enrolment of patients in clinical trials. New treatments, aiming to clear Aβ from the brain parenchyma or to reduce Aβ production and aggregation, are dependent on diagnostic tools to follow changes in brain Aβ levels in vivo

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