PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition

Poisnel, Géraldine; Dhilly, Martine; Moustié, Olivier; Delamare, Jérôme; Abbas, Ahmed M.; Guilloteau, Denis; Barré, Louisa

doi:10.1016/j.neurobiolaging.2011.12.024

Cited by 68 publications

(42 citation statements)

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“…The differences in Aβ plaque structure and deposition between animal models of AD could explain these differences obtained with the same tracer. Our study indicates that [ 18 F]AV-45 seems more sensitive than was also able to accumulate in the cortex and hippocampus at 8 and 12 months-of-age (Poisnel et al 2012). Another fluorinated tracer of plaques, [ 18 F]-florbetaben, had an increased cortical accumulation from 13 months in the APP-Swe model (Rominger et al 2013).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 55%

Amyloid load and translocator protein 18 kDa in APPswePS1-dE9 mice: a longitudinal study

Sérrière

Tauber

Vercouillie

et al. 2015

Neurobiology of Aging

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We studied concomitantly the level of neuroinflammation and β-amyloid (Aβ) load in the APPswePS1dE9 transgenic mouse model of Alzheimer's disease using positron emission tomography. The translocator protein 18 kDa (TSPO) tracer [(18)F]DPA-714 was used to measure neuroinflammation and [(18)F]AV-45 for Aβ load in mice at 6, 9, 12, 15, and 19 months of age. At 19 months, we also analyzed the neuroinflammatory and neuroanatomic status of mice brains. The main affected brain areas were the cortex and hippocampus, with a concomitant progression of neuroinflammation with increased amyloid burden. At 19 months, no increase in TSPO binding was observed in the cerebellum; immunostaining revealed W0-2-positive plaques, indicating that the amyloid deposits seemed not stimulate inflammation. This finding was in agreement with the observed level of microglia and astrocytes staining. Our findings provide a better understanding of the relationships between neuroinflammation and plaque accumulation in the course of the disease in this mouse model. The monitoring of both processes should be of value to validate potential therapeutic approaches.

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 55%

Amyloid load and translocator protein 18 kDa in APPswePS1-dE9 mice: a longitudinal study

Sérrière

Tauber

Vercouillie

et al. 2015

Neurobiology of Aging

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“…18 F-AV45 has been implemented in animal models to monitor changes in amyloid pathology with age (30,31). It has been shown that other amyloid tracers, such as 11 C-PiB and 18 F-florbetaben, are capable of detecting a treatment effect with amyloid-modulating therapies in transgenic mouse models (18,19).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease

et al. 2017

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In this study, we investigated the effects of chronic administration of an inhibitor of the b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) on Alzheimer-related pathology by multitracer PET imaging in transgenic APPPS1-21 (TG) mice. Methods: Wild-type (WT) and TG mice received vehicle or BACE inhibitor (60 mg/kg) starting at 7 wk of age. Outcome measures of brain metabolism, neuroinflammation, and amyloid-b pathology were obtained through small-animal PET imaging with 18 F-FDG, 18 F-peripheral benzodiazepine receptor ( 18 F-PBR), and 18 F-florbetapir ( 18 F-AV45), respectively. Baseline scans were acquired at 6-7 wk of age and follow-up scans at 4, 7, and 12 mo. 18 F-AV45 uptake was measured at 8 and 13 mo of age. After the final scans, histologic measures of amyloid-b (4G8), microglia (ionized calcium binding adaptor molecule 1), astrocytes (glial fibrillary acidic protein), and neuronal nuclei were performed. Results: TG mice demonstrated significant age-associated increases in 18 F-AV45 uptake. An effect of treatment was observed in the cortex (P 5 0.0014), hippocampus (P 5 0.0005), and thalamus (P , 0.0001). Histology confirmed reduction of amyloid-b pathology in TG-BACE mice. Regardless of treatment, TG mice demonstrated significantly lower 18 F-FDG uptake than WT mice in the thalamus (P 5 0.0004) and hippocampus (P 5 0.0332). Neuronal nucleus staining was lower in both TG groups in the thalamus and cortex. 18 F-PBR111 detected a significant age-related increase in TG mice (P , 0.0001) but did not detect the treatment-induced reduction in activated microglia as demonstrated by histology. Conclusion: Although 18 F-FDG, 18 F-PBR111, and 18 F-AV45 all detected pathologic alterations between TG and WT mice, only 18 F-AV45 could detect an effect of BACE inhibitor treatment. However, changes in WT binding of 18 F-AV45 undermine the specificity of this effect.

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“…1) (11,19). The binding potential (BP ND ) was calculated voxelwise in the cortical VOI from the entire dynamic recordings using a linear graphic method (20), with the cerebellum serving as the reference tissue.…”

Section: Image Reconstruction and Pet Data Analysesmentioning

confidence: 99%

“…Although current transgenic AD models obviously do not manifest all clinical and pathologic aspects of AD (6), they are nonetheless of heuristic value for the testing of interventions that address certain aspects of the disease, notably the formation of b-amyloid plaques. In this regard, molecular imaging of b-amyloid by PET has emerged as an important endpoint for assessing the extent of disease progression, although only limited imaging data are available in rodent AD models (7)(8)(9)(10)(11). The b-amyloid ligand 18 F-florbetaben, with high affinity for fibrillary b-amyloid in vitro, is currently in clinical development by Bayer Healthcare and Piramal Imaging (12)(13)(14) and has proven to have high sensitivity and specificity in clinical PET examinations for distinguishing AD patients from healthy control subjects (15).…”

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confidence: 99%

Longitudinal Assessment of Cerebral β-Amyloid Deposition in Mice Overexpressing Swedish Mutant β-Amyloid Precursor Protein Using ¹⁸F-Florbetaben PET

et al. 2013

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The progression of b-amyloid deposition in the brains of mice overexpressing Swedish mutant b-amyloid precursor protein (APPSwe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel b-amyloid tracer 18 Fflorbetaben. Methods: Groups of APP-Swe and age-matched wild-type (WT) mice (age range, 10-20 mo) were investigated. Dynamic emission recordings were acquired with a small-animal PET scanner during 90 min after the administration of 18 F-florbetaben (9 MBq, intravenously). After spatial normalization of individual PET recordings to common coordinates for mouse brain, binding potentials (BP ND ) and standardized uptake value ratios (SUVRs) were calculated relative to the cerebellum. Voxelwise analyses were performed using statistical parametric mapping (SPM). Histochemical analyses and ex vivo autoradiography were ultimately performed in a subset of animals as a gold standard assessment of b-amyloid plaque load. Results: SUVRs calculated from static recordings during the interval of 30-60 min after tracer injection correlated highly with estimates of BP ND based on the entire dynamic emission recordings. 18 F-florbetaben binding did not significantly differ in APP-Swe mice and WT animals at 10 and 13 mo of age. At 16 mo of age, the APP-Swe mice had a significant 7.9% increase (P , 0.01) in cortical 18 F-florbetaben uptake above baseline and at 20 mo there was a 16.6% increase (P , 0.001), whereas WT mice did not show any temporal changes in tracer uptake during the interval of follow-up. Voxelwise SPM analyses revealed the first signs of increased cortical binding at 13 mo and confirmed progressive binding increases in both the frontal and the temporal cortices (P , 0.001 uncorrected) to 20 mo. The SUVR strongly correlated with percentage plaque load (R 5 0.95, P , 0.001). Conclusion: In the first longitudinal PET study in an AD mouse model using the novel b-amyloid tracer 18 F-florbetaben, the temporal and spatial progression of amyloidogenesis in the brain of APP-Swe mice were sensitively monitored. This method should afford the means for preclinical testing of novel therapeutic approaches to the treatment of AD.

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PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition

Cited by 68 publications

References 50 publications

Amyloid load and translocator protein 18 kDa in APPswePS1-dE9 mice: a longitudinal study

Amyloid load and translocator protein 18 kDa in APPswePS1-dE9 mice: a longitudinal study

Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease

Longitudinal Assessment of Cerebral β-Amyloid Deposition in Mice Overexpressing Swedish Mutant β-Amyloid Precursor Protein Using ¹⁸F-Florbetaben PET

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PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition

Cited by 68 publications

References 50 publications

Amyloid load and translocator protein 18 kDa in APPswePS1-dE9 mice: a longitudinal study

Amyloid load and translocator protein 18 kDa in APPswePS1-dE9 mice: a longitudinal study

Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease

Longitudinal Assessment of Cerebral β-Amyloid Deposition in Mice Overexpressing Swedish Mutant β-Amyloid Precursor Protein Using 18F-Florbetaben PET

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Longitudinal Assessment of Cerebral β-Amyloid Deposition in Mice Overexpressing Swedish Mutant β-Amyloid Precursor Protein Using ¹⁸F-Florbetaben PET