Document Type

Article

Publication Date

1-1-2022

Publication Title

Alzheimer's & dementia (New York, N. Y.)

Keywords

JMG, 5XFAD, Alzheimer's disease, levetiracetam, preclinical testing

JAX Source

Alzheimers Dement (N Y) . 2022 Aug 23;8(1):e12329.

Volume

8

Issue

1

First Page

e12329

PMID

36016830

DOI

10.1002/trc2.12329

Grant

The authors would like to acknowledge the JAX Center for Bio- metric Analysis staff for assistance with chronic dosing studies and behavioral testing. They would also like to acknowledge the JAX Genome Technologies core for assistance with RNA extractions and sample processing for NanoString. The authors also wish to thank the IU Preclinical Model Testing Core at the IU Simon Cancer Cen- ter for the generous gift of mouse brains used in the formulations development and testing. The results published here are in whole or in part based on data obtained from the AD Knowledge Por- tal (https://adknowledgeportal.org). Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG36836 (RNAseq), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu. Mount Sinai Brain Bank data were generated from post mortem brain tissue collected through the Mount Sinai VA Med- ical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The Mayo RNAseq study data was led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Samples were provided from the following sources: The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research. The data for this study were funded through grant NIA U54AG054345.

Abstract

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, AUC, and CL/F, and a dose dependence in AUC. After chronic dosing at 10, 30, 56 mg/kg, PET/MRI tracer F-AV45, and F-fluorodeoxyglucose (F-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 F-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 F-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.

Comments

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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