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  • 1
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    Application of neurovascular uncoupling and whole brain network connectomics to assess the role of genetic and dietary risk factors in the LOAD2 mouse model
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. S1 ( 2023-06)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. S1 ( 2023-06)
    Abstract: As research efforts to discover and develop promising future therapeutics continues, the necessity to develop clinically significant Alzheimer’s disease (AD) mouse models and analysis is more important than ever. Method The study utilizes a novel MODEL‐AD (Model Organism Development and Evaluation for Late‐onset AD) mouse model that incorporates APOE4, Trem2 * R47H, and humanized amyloid‐beta (Aβ) allele into C57BL/6J (B6) mice to produce LOAD2. Two cohorts of male and female LOAD2 mice received either control or high fat diet (HFD) followed by brain metabolism imaging using 18F‐FDG PET/CT. Brain regions were segmented using the Paxinos‐Franklin atlas and analyzed using a whole brain neurovascular uncoupling and connectivity approach. To do this, we computed z‐score statistics for all mice relative their control diet group, and conducted hierarchical modularization of all 28 brain regions and statically compared results across sex and high‐risk diet in 12‐month‐old mice. Result An initial network analysis detected metabolic hypo‐perfusion and metabolism for female mice, while males showed neurovascular uncoupling. Hierarchical analysis revealed primary modules within the whole brain network. These primary modules were then further modularized to yield a final breakdown of six secondary sub‐modules consisting of 3‐7 brain regions. Predominate functional associations of the sub‐modules’ brain regions were sensory (S) and learning (L), while sub‐module 2.1 had the strongest visual (V) representation. Statistical analysis of the six sub‐modules exhibited significant, module‐, sex‐, and dietary‐dependent effect for LOAD2 mice on high fat diet (HFD) by 12mo. Conclusion The incorporation of APOE4, Trem2 * R47H, and humanized Ab sequence in combination with HFD induced age‐dependent LOAD‐relevant changes in neurovascular coupling and whole brain network connectivity consistent with known brain circuit variations observed clinically. These findings support application of this newer LOAD2 mouse model to improve knowledge regarding disease mechanism. Additionally, our connectivity analysis approach shows promise for implementation in future therapeutic development and testing.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.S1
    DOI: 10.1002/alz.065967
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2201940-6
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  • 2
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    Metabolic and Cerebrovascular Perturbations in the 5xFAD Mouse Model of Alzheimer’s Disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S3 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S3 ( 2022-12)
    Abstract: The Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium seeks to develop the next generation of AD models based on human data. A popular model of familial AD is the 5xFAD mouse. It is characterized by early amyloid‐β deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic aspects over its lifespan. Method Males and females 5xFAD and WT littermates underwent in vivo 18 F‐FDG‐PET imaging at 4, 6, and 12 months to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. Brains were analyzed for vascular characteristics such as vessel and junction density, vessel length, network complexity, number and diameter of collaterals. Result Our analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but interestingly their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was significantly decreased at 8 and 12 months in 5xFAD mice compared to WT; primarily driven by males. Analysis of 18 F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial somatosensory and visual cortices. Broadly, 5xFAD males had increased 18 F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics. Conclusion The 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐β deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18 F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S3
    DOI: 10.1002/alz.061565
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 3
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    Cerebral perfusion and glucose metabolism profiling reveal special phenotypes in the hAPOE3, hAPOE4, Trem2 risk, and doubled risks mice
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S3 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S3 ( 2022-12)
    Abstract: Alzheimer’s disease (AD) is the most common cause of dementia in the United States. Approximately 95% of patients have sporadic Late‐Onset AD (LOAD) which lacks an inheritance pattern. Therefore, identifying phenotypic patterns is critical for understanding disease progression. Among all the genetic markers which being identified as AD risks, and APOE4 confers the strongest one. The GWAS analysis also revealed a LOAD‐associated locus on the gene of TREM2. As the microglial receptor of APOE, the R47H variant on TREM2 increases the AD risk. In this study, how these risk alleles affect the brain phenotypes were assessed by MODEL‐AD. Method We established an analytical scheme which elucidates the cerebral perfusion and metabolism profiles across 27 brain regions by using 64 Cu‐PTSM and 18 F‐FDG PET imaging platform in the mice with wild‐type, humanized APOE3 (hAPO ε3/ ε3 ), humanized APOE4 (hAPO ε4/ ε4 ), TREM2 risk (Trem2 R47H/R47H ), and doubled risks (hAPO ε4/ ε4 :Trem2 R47H/R47H ) alleles. Also, RNA‐seq results from the hemisphere samples were used to conduct the correlation between PET measurements and the gene expression changes from each animal cohort. Result Longitudinal analysis (4mo animals as reference) revealed aging effects in each cohort. The male hAPOE4 mice and both sexes of Trem2 risk animals had hypo‐perfusion and metabolism, while female hAPOE4 mice showed an uncoupled hyper‐perfusion and hypo‐metabolism phenotype. In the doubled risks mice, perfusion and metabolism showed a mixed regional‐dependent phenotype. Cross‐sectional analysis (wildtype mice as reference) showed the effects of humanized genes. A reduction in glucose metabolism was discovered. Intriguingly, male risks mice also showed reduced in perfusion, while the female mice showed a metabolic uncoupling profile. Cross‐sectional analysis (hAPOE3 mice as reference) showed the effects of risk alleles. An overall reduction in both perfusion and metabolism was discovered in all animal cohorts. To confirm these findings, RNAseq showed the genes involved in cerebral perfusion, glucose transportation, and metabolism regulation were altered, which are consistent with the findings. Conclusion These data suggest that the new perfusion‐metabolism strategy may help to identify AD‐related patterns. Moreover, they replicate clinical manifestations of subjects with the same variants. Finally, additional studies are needed to elucidate the mechanisms and etiology of this uncoupling phenomenon.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S3
    DOI: 10.1002/alz.063682
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 4
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    Lifespan diffusion MRI reveals structural abnormalities in the 5xFAD model of Alzheimer’s Disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: The Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium has been established to develop the next generation of Alzheimer’s disease (AD) models based on human genomic findings. As new models are developed, phenotypic data are compared to established models, including the 5xFAD mouse model. We undertook measurements of diffusion metrics to characterize the temporal alterations in brain structure in male and female 5xFAD mice, including connectivity analysis between the hippocampus and infralimbic prefrontal cortex (PFC). Method 5xFAD mice were compared to age‐matched littermates (C57BL/6J, WT) at 4, 8, and 12 months (mo). Mice underwent high resolution diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) at 9.4T (5 B0, 30 directions b=3000 mm 2 /sec) to assess regional white and gray matter. Regional tissue features were extracted from fractional anisotropy (FA), radial (RD), axial (AxD) and mean diffusivity (MD) parametric maps. Tractography was performed based on the AMBMC mouse atlas. 18F‐AV45 PET was performed in a separate cohort at 4, 6, and 12mo to quantitate amyloid β (Aβ) load. Result Elevated FA within hippocampal CA1 was first observed in 5xFAD males at 8mo, but at 12mo 5xFAD females had increased FA in bilateral CA1 compared to WT mice. Connectivity between CA1 and PFC found 12mo 5xFAD females had significantly increased RD along the tract with concomitant increases in MD and AxD. AV45‐PET uptake was increased at 6mo (∼20%) and remained elevated at 12mo (∼25%) in the PFC in male and female 5xFAD compared to WT. In the hippocampus there was a ∼20% increase in AV45 binding at 6mo, that then declines by 12mo in 5xFAD mice. Conclusion Phenotyping of mouse models using DTI identifies altered brain connectivity and regional tissue modifications that may be indicative of increasing Aβ deposition. These data support that increasing Aβ deposition results in altered DTI metrics and connectivity using clinically relevant imaging modalities.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.062637
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 5
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    Pharmacodynamics Assessment of Aducanumab in 5XFAD mice: A MODEL‐AD PTC Study
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S4 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
    Abstract: The Preclinical Testing Core (PTC) of the Model Organism Development for Evaluation of Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a rigorous preclinical drug testing strategy with go/no‐go decision points that permits unbiased assessments of therapeutic agents. As part of the pipeline validation, the chimeric murinized therapeutic antibody aducanumab (chAducanumab), was selected for evaluation in 5XFAD mice. Methods Initial PK modeling and simulation was guided by literature and Aβ reductions from a pilot cohort of 9 month aged 5XFAD mice following 1x/week treatment of 30 mg/kg chAducanumab for 4 weeks. These pilot data were used to inform the chronic dosing regimen for the PD study which started at an age in 5XFAD mice where significant amyloid plaque accumulation was present (9 mos). PD endpoints (n=10‐12/sex/genotype/treatment) were assessed at the conclusion of chronic treatment, and included: 18‐FDG and 18F‐AV45 PET/CT, autoradiography, immunohistochemistry, AB40 and AB42 in plasma and brain fractions, and a behavioral battery. An additional cohort was enrolled for comprehensive cognitive testing using touchscreen learning and pattern separation tasks and evaluated for electroencephalography (EEG) activity using wireless telemetry. Results PK/PD modeling revealed slow clearance of chAducanumab following IP dosing with a T1/2 of ∼2.5 days. Therefore, the dose regimen for chronic PD studies included 0.1, 1.56, and 30 mg/kg administered 1x weekly for 12 weeks. Treatment with chAducanumab resulted in dose‐ and sex‐dependent reduction in amyloid deposition via 18F‐AV45 PET. Glucose uptake via 18F‐FDG PET similarly showed a dose dependent reversal of glycolytic loss in key brain regions. Cognitive assessments indicated no effect on learning however an improvement in pattern separation was observed with chAducanumab in females but not males. EEG analysis revealed improvements in delta, alpha, and beta oscillations with chAducanumab treatment. Multi‐omics analysis are in progress. Conclusions chAducanumab treatment in 5XFAD mice resulted in the expected reductions in brain amyloid consistent with clinical findings. Moreover, chAducanumab showed a unique glycolytic restoration profile in 5XFAD mice and improvements in some aspects of cognitive function. Together these data positively support pipeline validation of the MODEL‐AD PTC for evaluating therapeutic antibodies.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S4
    DOI: 10.1002/alz.064606
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 6
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    In Vivo UTE-MRI Reveals Positive Effects of Raloxifene on Skeletal-Bound Water in Skeletally Mature Beagle Dogs : MEASURING SKELETAL-BOUND WATER IN RALOXIFENE-TREATED DOGS
    Wiley ; 2015
    In:  Journal of Bone and Mineral Research Vol. 30, No. 8 ( 2015-08), p. 1441-1444
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 30, No. 8 ( 2015-08), p. 1441-1444
    Type of Medium: Online Resource
    ISSN: 0884-0431
    URL: Article
    DOI: 10.1002/jbmr.2470
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2008867-X
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  • 7
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    The 677C 〉 T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice
    SAGE Publications ; 2022
    In:  Journal of Cerebral Blood Flow & Metabolism Vol. 42, No. 12 ( 2022-12), p. 2333-2350
    Details
    In: Journal of Cerebral Blood Flow & Metabolism, SAGE Publications, Vol. 42, No. 12 ( 2022-12), p. 2333-2350
    Abstract: Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimer’s disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677 C  〉  T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR 677C  〉  T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr 677C  〉  T allele on the C57BL/6J background ( Mthfr 677C  〉  T ) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr 677C  〉  T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity is also reduced in the Mthfr 677C  〉  T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density, pericyte number and increased GFAP-expressing astrocytes in frontal cortex. Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data support a mechanism by which variations in MTHFR perturb cerebrovascular health laying the foundation to incorporate our new Mthfr 677C  〉  T mouse model in studies examining genetic susceptibility for cerebrovascular dysfunction in ADRDs.
    Type of Medium: Online Resource
    ISSN: 0271-678X , 1559-7016
    URL: Article
    DOI: 10.1177/0271678X221122644
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
    detail.hit.zdb_id: 2039456-1
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