Age- and Brain Region-Specific Changes of Glucose Metabolic Disorder, Learning, and Memory Dysfunction in Early Alzheimer's Disease Assessed in APP/PS1 Transgenic Mice Using 18F-FDG-PET.

Xue-Yuan Li,Xue-Yuan Li,Zhao-Hui Zhu,Hua Zhu,Ren-Zhi Wang,Zhan-Jing Wang,Wei-Wei Men,Zhan-Jing Wang,Hua Zhu,Jian-Feng Lei,Ren-Zhi Wang,Fu-Xing Zuo,Xin-Jie Bao,Fu-Xing Zuo,Xin-Jie Bao

doi:10.3390/ijms17101707

Abstract

Alzheimer’s disease (AD) is a leading cause of dementia worldwide, associated with cognitive deficits and brain glucose metabolic alteration. However, the associations of glucose metabolic changes with cognitive dysfunction are less detailed. Here, we examined the brains of APP/presenilin 1 (PS1) transgenic (Tg) mice aged 2, 3.5, 5 and 8 months using 18F-labed fluorodeoxyglucose (18F-FDG) microPET to assess age- and brain region-specific changes of glucose metabolism. FDG uptake was calculated as a relative standardized uptake value (SUVr). Morris water maze (MWM) was used to evaluate learning and memory dysfunction. We showed a glucose utilization increase in multiple brain regions of Tg mice at 2 and 3.5 months but not at 5 and 8 months. Comparisons of SUVrs within brains showed higher glucose utilization than controls in the entorhinal cortex, hippocampus, and frontal cortex of Tg mice at 2 and 3.5 months but in the thalamus and striatum at 3.5, 5 and 8 months. By comparing SUVrs in the entorhinal cortex and hippocampus, Tg mice were distinguished from controls at 2 and 3.5 months. In MWM, Tg mice aged 2 months shared a similar performance to the controls (prodromal-AD). By contrast, Tg mice failed training tests at 3.5 months but failed all MWM tests at 5 and 8 months, suggestive of partial or complete cognitive deficits (symptomatic-AD). Correlation analyses showed that hippocampal SUVrs were significantly correlated with MWM parameters in the symptomatic-AD stage. These data suggest that glucose metabolic disorder occurs before onset of AD signs in APP/PS1 mice with the entorhinal cortex and hippocampus affected first, and that regional FDG uptake increase can be an early biomarker for AD. Furthermore, hippocampal FDG uptake is a possible indicator for progression of Alzheimer’s cognition after cognitive decline, at least in animals.

Highlights

Alzheime’s disease (AD) is a leading cause of dementia in adults that affects 46.0 million people worldwide [1]
Because learning and memory is first affected in AD, this study investigated glucose metabolic changes in specific brain regions of amyloid precursor protein (APP)/ presenilin 1 (PS1) transgenic (Tg) mice of varying ages using positron emission tomography (PET) with learning and memory dysfunction resulting from early-stage AD
The increased SUVr values were more prominent at 3.5 mo, but significantly reduced to the same levels as the control in Tg mice of 5 and 8 mo. These findings suggest that PET detected early abnormalities in glucose metabolism in mice with AD and that FDG uptake can be an early biomarker for AD diagnosis

Summary

Introduction

Alzheime’s disease (AD) is a leading cause of dementia in adults that affects 46.0 million people worldwide [1]. Cognitive deficits are common in initial AD presentation, impairing daily performance and impacting quality of life, eventually ending in the death of the patient [2]. Cognitive deficits are often associated with brain metabolic alterations in AD [2,3], and studies using positron emission tomography (PET) have revealed brain glucose metabolic impairments in patients with AD [4]. A detailed analysis of the association between glucose metabolic dysfunction and specific cognitive impairments has not been conducted. Because learning and memory is first affected in AD, this study investigated glucose metabolic changes in specific brain regions of amyloid precursor protein (APP)/ presenilin 1 (PS1) transgenic (Tg) mice of varying ages using PET with learning and memory dysfunction resulting from early-stage AD

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Methods

Conclusion