title: 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 Using18F-FDG-PET.
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 using18F-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.
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. lixueyuan-82@163.com.
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Li
authors.affiliation: Center for Magnetic Resonance Imaging, Peking University, Beijing 100871, China. wmen@pku.edu.cn.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Men
authors.affiliation: Department of Pathology, Comparative Medical Center, Peking Union Medical College & Institute of Laboratory Animal Science, Chinese Academy of Medical Science, Beijing 100021, China. zhuhua0226@vip.sina.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Center for Medical Experiments and Testing, Capital Medical University, Beijing 100069, China. ccmu2013@sina.com.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Lei
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. zfx819_1986@163.com.
authors.forename: Fu-Xing
authors.initials: FX
authors.lastname: Zuo
authors.affiliation: Department of Pathology, Comparative Medical Center, Peking Union Medical College & Institute of Laboratory Animal Science, Chinese Academy of Medical Science, Beijing 100021, China. wangjingzhan@sina.com.
authors.forename: Zhan-Jing
authors.initials: ZJ
authors.lastname: Wang
authors.affiliation: Center for PET imaging, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. 13611093752@163.com.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. baoxinjie1@pumch.cn.
authors.forename: Xin-Jie
authors.initials: XJ
authors.lastname: Bao
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. wangrz@126.com.
authors.forename: Ren-Zhi
authors.initials: RZ
authors.lastname: Wang
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D003071:Cognition; D004195:Disease Models, Animal; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000032:analysis; D005947:Glucose / Q000032:analysis / Q000378:metabolism; D044882:Glucose Metabolism Disorders / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018782:Maze Learning; D008569:Memory Disorders / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D049268:Positron-Emission Tomography; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D019788:Fluorodeoxyglucose F18; D005947:Glucose
keywords: 18F-FDG PET; APP/PS1 mice; Alzheimer’s disease; cognitive dysfunction; glucose metabolism; hippocampus