Dataset Information

Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [¹⁸F]FDG-μPET Study.

ABSTRACT:

Background

The Apolipoprotein E (ApoE) alleles ɛ2, ɛ3, and ɛ4 are known to differentially modulate cerebral glucose metabolism and the risk for Alzheimer's disease (AD) via both amyloid-β (Aβ)-dependent and independent mechanisms.

Objective

We investigated the influence of ApoE on cerebral glucose metabolism in humanized APOE Targeted Replacement (TR) mice at ages that precede the comparison of Aβ parenchymal deposits in APOE4-TR mice.

Methods

Fludeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) measures were performed longitudinally in homozygous APOE-TR mice (APOE2, APOE3, APOE4; n = 10 for each group) at 3, 5, 11, and 15 months. Results were quantified using standard uptake values and analyzed statistically using a linear mixed effects model. Levels of the Aβ₄₀ and Aβ₄₂ peptides were quantified ex vivo using enzyme-linked immunosorbent assay (ELISA) at 15 months in the same animals.

Results

APOE2 mice (versus APOE3) showed a significant increase in glucose metabolism starting at 6 months, peaking at 9 months. No evidence of hypometabolism was apparent in any region or time point for APOE4 mice, which instead displayed a hypermetabolism at 15 months. Whole brain soluble Aβ₄₀ and Aβ₄₂ levels were not significantly different between genotypes at 15 months.

Conclusions

Introduction of human APOE alleles ɛ2 and ɛ4 is sufficient to produce alterations in brain glucose metabolism in comparison to the control allele ɛ3, without a concomitant alteration in Aβ₄₀ and Aβ₄₂ levels. These results suggest novel Aβ-independent metabolic phenotypes conferred by ɛ2 and ɛ4 alleles and have important implications for preclinical studies using TR-mice.

SUBMITTER: Venzi M

PROVIDER: S-EPMC6159693 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [<sup>18</sup>F]FDG-μPET Study.

Venzi Marcello M Tóth Miklós M Häggkvist Jenny J Bogstedt Anna A Rachalski Adeline A Mattsson Anna A Frumento Paolo P Farde Lars L

Journal of Alzheimer's disease reports 20171116 1

<h4>Background</h4>The Apolipoprotein E (ApoE) alleles <i>ɛ</i>2, <i>ɛ</i>3, and <i>ɛ</i>4 are known to differentially modulate cerebral glucose metabolism and the risk for Alzheimer's disease (AD) via both amyloid-β (Aβ)-dependent and independent mechanisms.<h4>Objective</h4>We investigated the influence of ApoE on cerebral glucose metabolism in humanized APOE Targeted Replacement (TR) mice at ages that precede the comparison of Aβ parenchymal deposits in APOE4-TR mice.<h4>Methods</h4>Fludeoxyg ...[more]

PMID: 30480236

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Project description:BackgroundCardiac arrest (CA) patients who survived by cardiopulmonary resuscitation (CPR) can present different levels of neurological deficits ranging from minor cognitive impairments to persistent vegetative state and brain death. The pathophysiology of the resulting brain injury is poorly understood, and whether changes in post-CA brain metabolism contribute to the injury are unknown. Here we utilized [18F]fluorodeoxyglucose (FDG)-Positron emission tomography (PET) to study in vivo cerebral glucose metabolism 72 h following CA in a murine CA model.MethodsAnesthetized and ventilated adult C57BL/6 mice underwent 12-min KCl-induced CA followed by CPR. Seventy-two hours following CA, surviving mice were intraperitoneally injected with [18F]FDG (~ 186 µCi/200 µL) and imaged on Molecubes preclinical micro-PET/computed tomography (CT) imaging systems after a 30-min awake uptake period. Brain [18F]FDG uptake was determined by the VivoQuant software on fused PET/CT images with the 3D brain atlas. Upon completion of Positron emission tomography (PET) imaging, remaining [18F]FDG radioactivity in the brain, heart, and liver was determined using a gamma counter.ResultsGlobal increases in brain [18F]FDG uptake in post-CA mice were observed compared to shams and controls. The median standardized uptake value of [18F]FDG for CA animals was 1.79 versus sham 1.25 (p < 0.05) and control animals 0.78 (p < 0.01). This increased uptake was consistent throughout the 60-min imaging period and across all brain regions reaching statistical significance in the midbrain, pons, and medulla. Biodistribution analyses of various key organs yielded similar observations that the median [18F]FDG uptake for brain was 7.04%ID/g tissue for CA mice versus 5.537%ID/g tissue for sham animals, p < 0.05).ConclusionsThis study has successfully applied [18F]FDG-PET/CT to measure changes in brain metabolism in a murine model of asystolic CA. Our results demonstrate increased [18F]FDG uptake in the brain 72 h following CA, suggesting increased metabolic demand in the case of severe neurological injury. Further study is warranted to determine the etiology of these changes.

Project description:BackgroundQuantification of the cerebral metabolic rate of glucose (CMRGlu) by dynamic [18F]FDG PET requires invasive arterial sampling. Alternatives to using an arterial input function (AIF) include the simultaneous estimation (SIME) approach, which models the image-derived input function (IDIF) by a series of exponentials with coefficients obtained by fitting time activity curves (TACs) from multiple volumes-of-interest. A limitation of SIME is the assumption that the input function can be modelled accurately by a series of exponentials. Alternatively, we propose a SIME approach based on the two-tissue compartment model to extract a high signal-to-noise ratio (SNR) model-derived input function (MDIF) from the whole-brain TAC. The purpose of this study is to present the MDIF approach and its implementation in the analysis of animal and human data.MethodsSimulations were performed to assess the accuracy of the MDIF approach. Animal experiments were conducted to compare derived MDIFs to measured AIFs (n = 5). Using dynamic [18F]FDG PET data from neurologically healthy volunteers (n = 18), the MDIF method was compared to the original SIME-IDIF. Lastly, the feasibility of extracting parametric images was investigated by implementing a variational Bayesian parameter estimation approach.ResultsSimulations demonstrated that the MDIF can be accurately extracted from a whole-brain TAC. Good agreement between MDIFs and measured AIFs was found in the animal experiments. Similarly, the MDIF-to-IDIF area-under-the-curve ratio from the human data was 1.02 ± 0.08, resulting in good agreement in grey matter CMRGlu: 24.5 ± 3.6 and 23.9 ± 3.2 mL/100 g/min for MDIF and IDIF, respectively. The MDIF method proved superior in characterizing the first pass of [18F]FDG. Groupwise parametric images obtained with the MDIF showed the expected spatial patterns.ConclusionsA model-driven SIME method was proposed to derive high SNR input functions. Its potential was demonstrated by the good agreement between MDIFs and AIFs in animal experiments. In addition, CMRGlu estimates obtained in the human study agreed to literature values. The MDIF approach requires fewer fitting parameters than the original SIME method and has the advantage that it can model the shape of any input function. In turn, the high SNR of the MDIFs has the potential to facilitate the extraction of voxelwise parameters when combined with robust parameter estimation methods such as the variational Bayesian approach.

Dataset Information

Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [¹⁸F]FDG-μPET Study.

Background

Objective

Methods

Results

Conclusions

Publications

Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [<sup>18</sup>F]FDG-μPET Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [18F]FDG-μPET Study.

Background

Objective

Methods

Results

Conclusions

Publications

Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [<sup>18</sup>F]FDG-μPET Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [¹⁸F]FDG-μPET Study.