Browsing by Author "Persohn, Scott C."

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    Brain metabolic network covariance and aging in a mouse model of Alzheimer's disease
    (Wiley, 2024) Chumin, Evgeny J.; Burton, Charles P.; Silvola, Rebecca; Miner, Ethan W.; Persohn, Scott C.; Veronese, Mattia; Territo, Paul R.; Medicine, School of Medicine
    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.
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    Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODEL-AD preclinical testing core study
    (Wiley, 2022-08-23) Onos, Kristen D.; Quinney, Sara K.; Jones, David R.; Masters, Andrea R.; Pandey, Ravi; Keezer, Kelly J.; Biesdorf, Carla; Metzger, Ingrid F.; Meyers, Jill A.; Peters, Johnathon; Persohn, Scott C.; McCarthy, Brian P.; Bedwell, Amanda A.; Figueiredo, Lucas L.; Cope, Zackary A.; Sasner, Michael; Howell, Gareth R.; Williams, Harriet M.; Oblak, Adrian L.; Lamb, Bruce T.; Carter, Gregory W.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Obstetrics and Gynecology, School of Medicine
    Introduction: Hyperexcitability and epileptiform activity are commonplace in Alzheimer's disease (AD) patients and associated with impaired cognitive function. The anti-seizure drug levetiracetam (LEV) is currently being evaluated in clinical trials for ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of our studies was to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship with LEV in an amyloidogenic mouse model of AD to enable predictive preclinical to clinical translation, using the rigorous preclinical testing pipeline of the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease Preclinical Testing Core. Methods: A multi-tier approach was applied that included quality assurance and quality control of the active pharmaceutical ingredient, PK/PD modeling, positron emission tomography/magnetic resonance imaging (PET/MRI), functional outcomes, and transcriptomics. 5XFAD mice were treated chronically with LEV for 3 months at doses in line with those allometrically scaled to the clinical dose range. Results: Pharmacokinetics of LEV demonstrated sex differences in Cmax, AUC0-∞, and CL/F, and a dose dependence in AUC0-∞. After chronic dosing at 10, 30, 56 mg/kg, PET/MRI tracer 18F-AV45, and 18F-fluorodeoxyglucose (18F-FDG) showed specific regional differences with treatment. LEV did not significantly improve cognitive outcomes. Transcriptomics performed by nanoString demonstrated drug- and dose-related changes in gene expression relevant to human brain regions and pathways congruent with changes in 18F-FDG uptake. Discussion: This study represents the first report of PK/PD assessment of LEV in 5XFAD mice. Overall, these results highlighted non-linear kinetics based on dose and sex. Plasma concentrations of the 10 mg/kg dose in 5XFAD overlapped with human plasma concentrations used for studies of mild cognitive impairment, while the 30 and 56 mg/kg doses were reflective of doses used to treat seizure activity. Post-treatment gene expression analysis demonstrated LEV dose-related changes in immune function and neuronal-signaling pathways relevant to human AD, and aligned with regional 18F-FDG uptake. Overall, this study highlights the importance of PK/PD relationships in preclinical studies to inform clinical study design. Highlights: Significant sex differences in pharmacokinetics of levetiracetam were observed in 5XFAD mice. Plasma concentrations of 10 mg/kg levetiracetam dose in 5XFAD overlapped with human plasma concentration used in the clinic. Drug- and dose-related differences in gene expression relevant to human brain regions and pathways were also similar to brain region-specific changes in 18F-fluorodeoxyglucose uptake.
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    The 677C > T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice
    (Sage, 2022-09-01) Reagan , Alaina M.; Christensen, Karen E.; Graham, Leah C.; Bedwell, Amanda A.; Eldridge, Kierra; Speedy, Rachael; Figueiredo, Lucas L.; Persohn, Scott C.; Bottiglieri, Teodoro; Nho, Kwangsik; Sasner, Michael; Territo, Paul R.; Rozen, Rima; Howell, Gareth R.; Medicine, School of Medicine
    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 MTHFR677C > T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C > T allele on the C57BL/6J background (Mthfr677C > T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C > T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity is also reduced in the Mthfr677C > 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 Mthfr677C > T mouse model in studies examining genetic susceptibility for cerebrovascular dysfunction in ADRDs.
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    The 677C > T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice
    (Sage, 2022) Reagan, Alaina M.; Christensen, Karen E.; Graham, Leah C.; Bedwell, Amanda A.; Eldridge, Kierra; Speedy, Rachael; Figueiredo, Lucas L.; Persohn, Scott C.; Bottiglieri, Teodoro; Nho, Kwangsik; Sasner, Michael; Territo, Paul R.; Rozen, Rima; Howell, Gareth R.; Medicine, School of Medicine
    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 MTHFR677C > T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C > T allele on the C57BL/6J background (Mthfr677C > T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C > T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity is also reduced in the Mthfr677C > 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 Mthfr677C > T mouse model in studies examining genetic susceptibility for cerebrovascular dysfunction in ADRDs.