In vivo molecular neuroimaging of glucose utilization and its association with fibrillar amyloid-β load in aged APPPS1-21 mice

Waldron, Ann-Marie; Wintmolders, Cindy; Bottelbergs, Astrid; Kelley, Jonathan; Schmidt, Mark E.; Stroobants, Sigrid; Langlois, Xavier; Staelens, Steven

doi:10.1186/s13195-015-0158-6

Cited by 29 publications

(29 citation statements)

References 57 publications

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“…*P , 0.05; **P , 0.01; ***P , 0.001; ****P , 0.0001. significant genotypic differences in 18 F-AV45 uptake in TG mice in this study contrast with our previous investigation, which did not find significant differences in 18 F-AV45 uptake in 12-mo-old TG mice. This difference is likely attributable to the higher number of animals in the current study (32).…”

Section: Discussionmentioning

confidence: 55%

“…We previously demonstrated hypometabolism in 12-mo-old TG mice with in vivo 18 F-FDG imaging, confirmed by ex vivo 14 C-2-deoxyglucose autoradiography (32). Assuming that hypometabolism is a downstream consequence of amyloid-b pathology, we hypothesized that reductions in 18 F-FDG in TG mice would worsen with increasing age and that lowering amyloid-b pathology would prevent or slow changes in brain metabolism.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 55%

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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“…Being fluorinated, it has the added benefits of increased availability in comparison to its predecessor, [ 11 C]-PiB. However, one disadvantage of [ 18 F]-AV45 is its notably lower dynamic range due to high non-specific white matter binding [41], which we have previously shown to result in smaller differences between WT and transgenic mice [16]. Herein, as part of our investigations into the sensitivity of [ 18 F]-AV45, we aimed to assess the production and brain uptake of radiometabolites.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model

Waldron

wyffels

Verhaeghe

et al. 2016

JAD

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We aimed to monitor the timing of amyloid-β deposition in relation to changes in brain function using in vivo imaging with [18F]-AV45 and [18F]-FDG in a mouse model of Alzheimer’s disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [18F]-AV45 and [18F]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [18F]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated to ex vivo measures of amyloid burden. The metabolism of [18F]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [18F]-AV45. The observed trajectory of [18F]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [18F]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [18F]-FDG was not associated with aging in TASTPM mice. Moreover, [18F]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-β is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice.

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“…Brain tissue was cryosectioned (14 µm) and exposed to phosphor imaging plates (Fujifilm Plate BAS-TR2025, Fujifilm, Tokyo, Japan). Quantitative analysis of plates was performed using Multi Gauge 3.2 phosphorimager software (Fujifilm) as described elsewhere (Miyamoto et al 2000, Waldron et al 2015.…”

Section: Ex Vivo Autoradiography Analysis Of Hypothalamic Glucose Uptakementioning

confidence: 99%

Reduced metabolism in the hypothalamus of the anorectic anx/anx mouse

Bergström

Lindfors

Svedberg

et al. 2017

Journal of Endocrinology

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The anorectic mouse exhibits a mitochondrial complex I dysfunction that is related to aberrant expression of hypothalamic neuropeptides and transmitters regulating food intake. Hypothalamic activity, i.e. neuronal firing and transmitter release, is dependent on glucose utilization and energy metabolism. To better understand the role of hypothalamic activity in anorexia, we assessed carbohydrate and high-energy phosphate metabolism, and , in the hypothalamus. In the fasted state, hypothalamic glucose uptake in the mouse was reduced by ~50% of that seen in wild-type (wt) mice ( < 0.05). Under basal conditions, hypothalamus ATP and glucose 6-P contents were similar to those in wt hypothalamus, whereas phosphocreatine was elevated (~2-fold; < 0.001) and lactate was reduced (~35%; < 0.001). The hypothalamus had elevated total AMPK (~25%; < 0.05) and GLUT4 (~60%; < 0.01) protein contents, whereas GLUT1 and GLUT3 were similar to that of wt hypothalamus. Interestingly, the activation state of AMPK (ratio of phosphorylated AMPK/total AMPK) was significantly decreased in hypothalamus of the mouse (~60% of that in wt; < 0.05). Finally, during metabolic stress (ischemia), accumulation of lactate (measure of glycolysis) and IMP and AMP (breakdown products of ATP) were ~50% lower in vs wt hypothalamus. These data demonstrate that carbohydrate and high-energy phosphate utilization in the hypothalamus are diminished under basal and stress conditions. The decrease in hypothalamic metabolism may contribute to the anorectic behavior of the mouse, i.e. its inability to regulate food intake in accordance with energy status.

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In vivo molecular neuroimaging of glucose utilization and its association with fibrillar amyloid-β load in aged APPPS1-21 mice

Cited by 29 publications

References 57 publications

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

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

Longitudinal Characterization of [18F]-FDG and [18F]-AV45 Uptake in the Double Transgenic TASTPM Mouse Model

Reduced metabolism in the hypothalamus of the anorectic anx/anx mouse

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