BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein e4 (APOEe4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS: All hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEe4/e4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 mo, while APOEe3/e4 demonstrated Type-2 uncoupling (increased glucose uptake, decreased perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEe4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.
Subcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer's disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core.
MODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models.
Abstract INTRODUCTION MODEL‐AD (Model Organism Development and Evaluation for Late‐Onset Alzheimer's Disease) is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory and progression of late‐onset Alzheimer's disease (LOAD) more accurately. METHODS We created the LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, and humanized amyloid‐beta (Aβ). Mice were subjected to a control diet or a high‐fat/high‐sugar diet (LOAD2+HFD). We assessed disease‐relevant outcome measures in plasma and brain including neuroinflammation, Aβ, neurodegeneration, neuroimaging, and multi‐omics. RESULTS By 18 months, LOAD2+HFD mice exhibited sex‐specific neuron loss, elevated insoluble brain Aβ42, increased plasma neurofilament light chain (NfL), and altered gene/protein expression related to lipid metabolism and synaptic function. Imaging showed reductions in brain volume and neurovascular uncoupling. Deficits in acquiring touchscreen‐based cognitive tasks were observed. DISCUSSION The comprehensive characterization of LOAD2+HFD mice reveals that this model is important for preclinical studies seeking to understand disease trajectory and progression of LOAD prior to or independent of amyloid plaques and tau tangles. Highlights By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2+HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble Ab42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease‐relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age‐dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2+HFD mice also demonstrated deficits in acquisition of touchscreen‐based cognitive tasks.
Introduction Subcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer’s disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core. Methods Chronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing 18 F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling. Results Pharmacokinetics of LEV showed a sex and dose dependence in C max , CL/F, and AUC 0-∞ , with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18 F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e., positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent 18 F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling. Discussion This study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration-dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of 18 F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value toward informing clinical study design.
Abstract INTRODUCTION Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a human and financial impact for which few effective drugs exist to treat the disease. Advances in molecular imaging have enabled assessment of cerebral glycolytic metabolism, and network modeling of brain region have linked to alterations in metabolic activity to AD stage. METHODS We performed 18 F‐FDG positron emission tomography (PET) imaging in 4‐, 6‐, and 12‐month‐old 5XFAD and littermate controls (WT) of both sexes and analyzed region data via brain metabolic covariance analysis. RESULTS The 5XFAD model mice showed age‐related changes in glucose uptake relative to WT mice. Analysis of community structure of covariance networks was different across age and sex, with a disruption of metabolic coupling in the 5XFAD model. DISCUSSION The current study replicates clinical AD findings and indicates that metabolic network covariance modeling provides a translational tool to assess disease progression in AD models.
Abstract BACKGROUND Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS PET imaging was used to assess metabolism‐perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO‐term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type‐1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type‐2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. Highlights We developed a novel analytical method to analyze PET imaging of 18 F‐FDG and 64 Cu‐PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism‐perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type‐1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type‐2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.
