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Antibody-based in vivo PET imaging detects amyloid-? reduction in Alzheimer transgenic mice after BACE-1 inhibition.

ABSTRACT: Positron emission tomography (PET) used for visualizing amyloid-? (A?) pathology has become an important tool for specific clinical diagnosis of Alzheimer's disease (AD). However, all available amyloid PET radioligands, such as [11C]PiB, reflect levels of insoluble A? plaques, but do not capture soluble and protofibrillar A? forms. When measured with current PET ligands, the plaque load appears to be fairly static during clinical stages of AD, and may not be affected by A? reducing treatments. The aim of the present study was to investigate if a novel PET radioligand, based on an antibody directed towards soluble aggregates of A?, could be used to detect changes in A? levels during disease progression and after treatment with a ?-secretase (BACE-1) inhibitor. Methods: One set of transgenic mice (tg-ArcSwe, model of A? pathology) aged between 7 and 16 months were PET scanned with the A? protofibril selective radioligand [124I]RmAb158-scFv8D3 to follow progression of A? pathology in the brain. A second set of tg-ArcSwe mice, aged 10 months, were treated with BACE-1 inhibitor NB-360 for 3 months and compared to an untreated control group. A set of 10 months old tg-ArcSwe mice also underwent PET scanning, acting as a baseline group. Brain tissue was isolated after PET to determine levels of A? by ELISA and immunohistochemistry. Results: Concentration of [124I]RmAb158-scFv8D3 in tg-ArcSwe mice, measured in vivo with PET, increased with age and corresponded well with ex vivo autoradiography and A? immunohistochemistry. Tg-ArcSwe mice treated with NB-360 showed significantly lower in vivo PET signals than untreated animals, and were similar to the baseline 10 month old animals. The decreased [124I]RmAb158-scFv8D3 concentrations in NB-360 treated mice, quantified with PET, corresponded well with decreased A? levels measured in post mortem brain. Conclusion: A number of treatments for AD are currently studied in phase 2 and 3 clinical trials but there are limited possibilities to study their effects on the important, non-fibrillar A? forms in vivo. This study demonstrates the ability of the A? protofibril selective radioligand [124I]RmAb158-scFv8D3 to follow disease progression and detect treatment effects with PET imaging in tg-ArcSwe mice.

SUBMITTER: Meier SR

PROVIDER: S-EPMC6278900 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Antibody-Based In Vivo PET Imaging Detects Amyloid-β Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition.

Meier Silvio R SR Syvänen Stina S Hultqvist Greta G Fang Xiaotian T XT Roshanbin Sahar S Lannfelt Lars L Neumann Ulf U Sehlin Dag D

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20180531 12

Visualization of amyloid-β (Aβ) pathology with PET has become an important tool for making a specific clinical diagnosis of Alzheimer disease (AD). However, the available amyloid PET radioligands, such as <sup>11</sup>C-Pittsburgh compound B, reflect levels of insoluble Aβ plaques but do not capture soluble and protofibrillar Aβ forms. Furthermore, the plaque load appears to be fairly static during clinical stages of AD and may not be affected by Aβ-reducing treatments. The aim of the present st ...[more]

PMID: 29853653

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Project description:Aims/hypothesisIslet amyloid deposits contribute to beta cell dysfunction and death in most individuals with type 2 diabetes but non-invasive methods to determine the presence of these pathological protein aggregates are currently not available. Therefore, we examined whether florbetapir, a radiopharmaceutical agent used for detection of amyloid-β deposits in the brain, also allows identification of islet amyloid in the pancreas.MethodsSaturation binding assays were used to determine the affinity of florbetapir for human islet amyloid polypeptide (hIAPP) aggregates in vitro. Islet amyloid-prone transgenic mice that express hIAPP in their beta cells and amyloid-free non-transgenic control mice were used to examine the ability of florbetapir to detect islet amyloid deposits in vitro, in vivo and ex vivo. Mice or mouse pancreases were subjected to autoradiographic, histochemical and/or positron emission tomography (PET) analyses to assess the utility of florbetapir in identifying islet amyloid.ResultsIn vitro, florbetapir bound synthetic hIAPP fibrils with a dissociation constant of 7.9 nmol/l. Additionally, florbetapir bound preferentially to amyloid-containing hIAPP transgenic vs amyloid-free non-transgenic mouse pancreas sections in vitro, as determined by autoradiography (16,475 ± 5581 vs 5762 ± 575 density/unit area, p < 0.05). In hIAPP transgenic and non-transgenic mice fed a high-fat diet for 1 year, intravenous administration of florbetapir followed by PET scanning showed that the florbetapir signal was significantly higher in amyloid-laden hIAPP transgenic vs amyloid-free non-transgenic pancreases in vivo during the first 5 min of the scan (36.83 ± 2.22 vs 29.34 ± 2.03 standardised uptake value × min, p < 0.05). Following PET, pancreases were excised and florbetapir uptake was determined ex vivo by γ counting. Pancreatic uptake of florbetapir was significantly correlated with the degree of islet amyloid deposition, the latter assessed by histochemistry (r = 0.74, p < 0.001).Conclusions/interpretationFlorbetapir binds to islet amyloid deposits in a specific and quantitative manner. In the future, florbetapir may be useful as a non-invasive tool to identify islet amyloid deposits in humans.

Project description:IntroductionThe accumulation of amyloid-? is a pathological hallmark of Alzheimer's disease and is a target for molecular imaging probes to aid in diagnosis and disease monitoring. This study evaluated the feasibility of using a radiolabeled monoclonal anti-amyloid-? antibody (JRF/A?N/25) to non-invasively assess amyloid-? burden in aged transgenic mice (APPPS1-21) with ?PET imaging.MethodsWe investigated the antibody JRF/A?N/25 that binds to full-length A?. JRF/A?N/25 was radiolabeled with a [(89)Zr]-desferal chelate and intravenously injected into 12-13 month aged APPPS1-21 mice and their wild-type (WT) controls. Mice underwent in vivo ?PET imaging at 2, 4, and 7 days post injection and were sacrificed at the end of each time point to assess brain penetrance, plaque labeling, biodistribution, and tracer stability. To confirm imaging specificity we also evaluated brain uptake of a non-amyloid targeting [(89)Zr]-labeled antibody (trastuzumab) as a negative control, additionally we performed a competitive blocking study with non-radiolabeled Df-Bz-JRF/A?N/25 and finally we assessed the possible confounding effects of blood retention.ResultsVoxel-wise analysis of ?PET data demonstrated significant [(89)Zr]-Df-Bz-JRF/A?N/25 retention in APPPS1-21 mice at all time points investigated. With ex vivo measures of radioactivity, significantly higher retention of [(89)Zr]-Df-Bz-JRF/A?N/25 was found at 4 and 7 days pi in APPPS1-21 mice. Despite the observed genotypic differences, comparisons with immunohistochemistry revealed that in vivo plaque labeling was low. Furthermore, pre-treatment with Df-Bz-JRF/A?N/25 only partially blocked [(89)Zr]-Df-Bz-JRF/A?N/25 uptake indicative of a high contribution of non-specific binding.ConclusionAmyloid plaques were detected in vivo with a radiolabeled monoclonal anti-amyloid antibody. The low brain penetrance of the antibody in addition to non-specific binding prevented an accurate estimation of plaque burden. However, it should be noted that [(89)Zr]-Df-Bz-JRF/A?N/25 nevertheless demonstrated in vivo binding and strategies to increase brain penetrance would likely achieve better results.

Project description:BACKGROUND:Oxidation-specific epitopes (OSEs) are proinflammatory, and elevated levels in plasma predict cardiovascular events. OBJECTIVES:The purpose of this study was to develop novel positron emission tomography (PET) probes to noninvasively image OSE-rich lesions. METHODS:An antigen-binding fragment (Fab) antibody library was constructed from human fetal cord blood. After multiple rounds of screening against malondialdehyde-acetaldehyde (MAA) epitopes, the Fab LA25 containing minimal nontemplated insertions in the CDR3 region was identified and characterized. In mice, pharmacokinetics, biodistribution, and plaque specificity studies were performed with Zirconium-89 (89Zr)-labeled LA25. In rabbits, 89Zr-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. 18F-fluorodeoxyglucose PET and dynamic contrast-enhanced MR imaging were used to evaluate vessel wall inflammation and plaque neovascularization, respectively. Extensive ex vivo validation was carried out through a combination of gamma counting, near infrared fluorescence, autoradiography, immunohistochemistry, and immunofluorescence. RESULTS:LA25 bound specifically to MAA epitopes in advanced and ruptured human atherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of 89Zr-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. 18F-fluorodeoxyglucose PET, dynamic contrast-enhanced MR imaging, and near-infrared fluorescence signals were also significantly higher in atherosclerotic rabbit aortas compared with control aortas. Enhanced liver uptake was also noted in atherosclerotic animals, confirmed by the presence of MAA epitopes by immunostaining. CONCLUSIONS:89Zr-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions.

Dataset Information

Antibody-based in vivo PET imaging detects amyloid-? reduction in Alzheimer transgenic mice after BACE-1 inhibition.

Publications

Antibody-Based In Vivo PET Imaging Detects Amyloid-β Reduction in Alzheimer Transgenic Mice After BACE-1 Inhibition.

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