Impact of Donepezil on Brain Glucose Metabolism Assessed Using [18F]2-Fluoro-2-deoxy-D-Glucose Positron Emission Tomography Imaging in a Mouse Model of Alzheimer's Disease Induced by Intracerebroventricular Injection of Amyloid-Beta Peptide

Abstract

Translational methods are needed to monitor the impact of the Alzheimer's disease (AD) and therapies on brain function in animal models and patients. The formation of amyloid plaques was investigated using [¹⁸F]florbetapir autoradiography in a mouse model of AD consisting in unilateral intracerebroventricular (i.c.v) injection of amyloid peptide Aβ_25-35. Then, an optimized positron emission tomography (PET) imaging protocol using [¹⁸F]2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) was performed to estimate brain glucose metabolism: [¹⁸F]FDG was injected in awake animals to allow for 40 min brain uptake in freely moving mice. Anesthesia was then induced for 30 min PET acquisition to capture the slow and poorly reversible brain uptake of [¹⁸F]FDG. Impact of donepezil (0.25 mg/kg daily, 7 days, orally) on brain function was investigated in AD mice (n = 6 mice/group). Formation of amyloid plaques could not be detected using autoradiography. Compared with sham controls (injection of scramble peptide), significant decrease in [¹⁸F]FDG uptake was observed in the AD group in the subcortical volume of the ipsilateral hemisphere. Donepezil restored normal glucose metabolism by selectively increasing glucose metabolism in the affected subcortical volume but not in other brain regions. In mice, [¹⁸F]FDG PET imaging can be optimized to monitor impaired brain function associated with i.c.v injection of Aβ_25-35, even in the absence of detectable amyloid plaque. This model recapitulates the regional decrease in [¹⁸F]FDG uptake observed in AD patients. [¹⁸F]FDG PET imaging can be straightforwardly transferred to AD patients and may aid the development of certain therapies designed to restore the altered brain function in AD.

Keywords: Alzheimer’s disease; Alzheimer’s mouse model; PET imaging; awake brain imaging; donepezil; functional imaging (positron emission tomography).

FIGURE 1

Autoradiography of brain slices using the amyloid radioligand [¹⁸F]florbetapir in the mouse model of Alzheimer’s disease (AD). Brains were resected 10 days after intracerebroventricular injection (i.c.v) of amyloid peptide Aβ_25–35. Representative mouse brain sections of [¹⁸F]florbetapir binding within hippocampal and cortical region is shown in control and AD mice (in A). Quantitative in vitro analysis of [¹⁸F]florbetapir binding on autoradiograms of the i.c.v Aβ_25–35 mouse model was performed using n = 4 animals per group with four quantified brain sections each. Mean gray values normalized by regions of interest (ROI) area are presented (B). Ratios of [¹⁸F]florbetapir binding on injection side (ipsilateral, right) to contralateral side (left) is shown in panel (C). No significant differences in [¹⁸F]florbetapir binding in vitro was measured between control and AD group (ns; p > 0.05).

FIGURE 2

Representative brain [¹⁸F]2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) positron emission tomography (PET) images obtained in mice. In panel (A), [¹⁸F]FDG PET image is expressed as standardized uptake values (SUV), with SUV = tissue activity (kBq/cc)/[injected dose (kBq)/body weight (g)]. Uptake was determined in control mice, in a mouse model of Alzheimer’s disease (AD) consisting in intracerebroventricular (i.c.v) injection of amyloid peptide Aβ_25–35 (AD) and in mice that received i.c.v injection of amyloid peptide Aβ_25–35 treated with donepezil (AD + DPZ). Corresponding parametric SUVR images (PET signal is normalized by cerebellar uptake of radioactivity) are shown in panel (B). The cortical volume in delineated in white. A white arrow shows the subcortical volume with visually decreased SUVR in the right ipsilateral hemisphere compared with the contralateral hemisphere.

FIGURE 3

Quantitative brain [¹⁸F]2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) positron emission tomography (PET) data in selected brain region in mice. [¹⁸F]FDG brain uptake was expressed as standardized uptake values (SUV). Uptake was determined in control mice, in a mouse model of Alzheimer’s disease (AD) consisting in intracerebroventricular (i.c.v) injection of amyloid peptide Aβ_25–35 (AD) and in mice that received i.c.v injection of amyloid peptide Aβ_25–35 treated with donepezil (AD + DPZ). Data are reported as mean ± S.D (n = 6 per group). There were statistical differences on neither SUV values (in A) nor SUV values normalized by cerebellum uptake (SUVR, in B) between groups (ns; p > 0.05).

FIGURE 4

Parametric mapping of [¹⁸F]2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) brain uptake reflecting therapeutic response to donepezil. Positron emission tomography (PET) images in Standard Uptake Value (SUV) were normalized to radioactivity in the cerebellum. Statistical maps were overlaid to a mouse MRI template. Panel (A) shows regions with significant decrease in glucose metabolism (p < 0.05; threshold: 200 voxels) in a mouse model of Alzheimer’s disease (AD) obtained after unilateral intracerebroventricular injection of peptide Aβ_25–35 compared with control mice. Region with significant increase in brain glucose metabolism after DPZ (0.25 mg/kg daily, 7 days) treatment mice in shown in panel (B) (p < 0.05; threshold: 200 voxels). No differences was observed in the right hemisphere between control and AD mice treated with DPZ [0.25 mg/kg, in panel (C)].