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Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies.

Abstract

Alzheimer's disease (AD) is an age-related devastating neurodegenerative disorder, which severely impacts on the global economic development and healthcare system. Though AD has been studied for more than 100 years since 1906, the exact cause(s) and pathogenic mechanism(s) remain to be clarified. Also, the efficient disease-modifying treatment and ideal diagnostic method for AD are unavailable. Perturbed cerebral glucose metabolism, an invariant pathophysiological feature of AD, may be a critical contributor to the pathogenesis of this disease. In this review, we firstly discussed the features of cerebral glucose metabolism in physiological and pathological conditions. Then, we further reviewed the contribution of glucose transportation abnormality and intracellular glucose catabolism dysfunction in AD pathophysiology, and proposed a hypothesis that multiple pathogenic cascades induced by impaired cerebral glucose metabolism could result in neuronal degeneration and consequently cognitive deficits in AD patients. Among these pathogenic processes, altered functional status of thiamine metabolism and brain insulin resistance are highly emphasized and characterized as major pathogenic mechanisms. Finally, considering the fact that AD patients exhibit cerebral glucose hypometabolism possibly due to impairments of insulin signaling and altered thiamine metabolism, we also discuss some potential possibilities to uncover diagnostic biomarkers for AD from abnormal glucose metabolism and to develop drugs targeting at repairing insulin signaling impairment and correcting thiamine metabolism abnormality. We conclude that glucose metabolism abnormality plays a critical role in AD pathophysiological alterations through the induction of multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, and so forth. To clarify the causes, pathogeneses and consequences of cerebral hypometabolism in AD will help break the bottleneck of current AD study in finding ideal diagnostic biomarker and disease-modifying therapy.

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  • Authors+Show Affiliations

    ,

    Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.

    Source

    Progress in neurobiology 108: 2013 Sep pg 21-43

    MeSH

    Alzheimer Disease
    Biomarkers
    Brain Chemistry
    Diabetes Mellitus, Type 2
    Glucose
    Glucose Transport Proteins, Facilitative
    Humans
    Oxidative Stress
    Thiamine

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Review

    Language

    eng

    PubMed ID

    23850509

    Citation

    Chen, Zhichun, and Chunjiu Zhong. "Decoding Alzheimer's Disease From Perturbed Cerebral Glucose Metabolism: Implications for Diagnostic and Therapeutic Strategies." Progress in Neurobiology, vol. 108, 2013, pp. 21-43.
    Chen Z, Zhong C. Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol. 2013;108:21-43.
    Chen, Z., & Zhong, C. (2013). Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Progress in Neurobiology, 108, pp. 21-43. doi:10.1016/j.pneurobio.2013.06.004.
    Chen Z, Zhong C. Decoding Alzheimer's Disease From Perturbed Cerebral Glucose Metabolism: Implications for Diagnostic and Therapeutic Strategies. Prog Neurobiol. 2013;108:21-43. PubMed PMID: 23850509.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. AU - Chen,Zhichun, AU - Zhong,Chunjiu, Y1 - 2013/07/11/ PY - 2013/04/06/received PY - 2013/06/03/revised PY - 2013/06/18/accepted PY - 2013/7/16/entrez PY - 2013/7/16/pubmed PY - 2014/3/22/medline KW - (11)C-Pittsbergh compound KW - (18)F-fluorodeoxyglucose KW - 8-OHG KW - 8-hydroxyguanosine KW - AD KW - AD neuroimaging initiative KW - ADNI KW - ADP KW - AGEs KW - APOE KW - APP KW - APP C-terminal fragments KW - APP-CTFs KW - ATP KW - Advanced glycation endproducts KW - Alzheimer's disease KW - Apoptosis KW - Autophagy KW - Aβ KW - BBB KW - CHEIs KW - CMRglu KW - CNS KW - COX KW - CSF KW - Cerebral hypometabolism KW - Excitotoxicity KW - FDG KW - G6PDH KW - GLP-1 KW - GLUT KW - GSK-3 KW - Glucagon-like peptide-1 KW - Glycogen synthase kinase 3 KW - IDE KW - IGF-1 KW - IR KW - IR substrate-1 KW - IRS-1 KW - Insulin resistance KW - KGDHC KW - LTP KW - MAPK KW - MCI KW - MMSE KW - MR KW - Mitochondrial dysfunction KW - N-methyl-D-aspartic acid receptor KW - NFTs KW - NMDAR KW - NSAID KW - Oxidative stress KW - PDHC KW - PET KW - PI3K KW - PKM2 KW - PPP KW - PS1 KW - Peroxisome proliferator-activated receptors KW - PiB KW - Positron emission tomography KW - RAGE KW - ROS KW - STZ KW - T1DM KW - T2DM KW - TCA KW - TD KW - TDP KW - TDPase KW - TGF KW - TMP KW - TMPase KW - TPK KW - Tau KW - Thiamine KW - adenosine driphosphate KW - adenosine triphosphate KW - advanced glycation end products KW - amyloid precursor protein KW - apolipoprotein E KW - blood brain barrier KW - central nervous system KW - cerebral metabolic rate of glucose KW - cerebrospinal fluid KW - cholinesterase inhibitors KW - cytochrome c oxidase KW - glucagon-like peptide-1 KW - glucose transporter KW - glucose-6-phosphate dehydrogenase KW - glycogen synthase kinase-3 KW - insulin receptor KW - insulin-degrading enzyme KW - insulin-like growth factor-1 KW - long term potentiation KW - mTOR KW - magnetic resonance KW - mild cognitive impairment KW - mitogen-activated protein kinase KW - neurofibrillary tangles KW - non-steroidal anti-inflammatory drug KW - pentose phosphate pathway KW - phosphatidylinositide 3-kinases KW - positron emission tomography KW - presenilin-1 KW - pyruvate dehydrogenase complex KW - pyruvate kinase isozyme type M2 KW - rCBF KW - rCMRGlu KW - reactive oxygen species KW - regional CMRGlu KW - regional cerebral blood flow KW - streptozotocin KW - the Mini-Mental State Examination KW - the mammalian target of rapamycin KW - the receptor of AGEs KW - thiamine deficiency KW - thiamine diphosphatase KW - thiamine diphosphate KW - thiamine monophosphatase KW - thiamine monophosphate KW - thiamine pyrophosphokinase KW - transformation growth factor KW - tricarboxylic acid KW - type 1 diabetes mellitus KW - type 2 diabetes mellitus KW - α-ketoglutarate dehydrogenase complex KW - β-amyloid KW - γ-PPAR KW - γ-peroxisome proliferator-actived receptor SP - 21 EP - 43 JF - Progress in neurobiology JO - Prog. Neurobiol. VL - 108 N2 - Alzheimer's disease (AD) is an age-related devastating neurodegenerative disorder, which severely impacts on the global economic development and healthcare system. Though AD has been studied for more than 100 years since 1906, the exact cause(s) and pathogenic mechanism(s) remain to be clarified. Also, the efficient disease-modifying treatment and ideal diagnostic method for AD are unavailable. Perturbed cerebral glucose metabolism, an invariant pathophysiological feature of AD, may be a critical contributor to the pathogenesis of this disease. In this review, we firstly discussed the features of cerebral glucose metabolism in physiological and pathological conditions. Then, we further reviewed the contribution of glucose transportation abnormality and intracellular glucose catabolism dysfunction in AD pathophysiology, and proposed a hypothesis that multiple pathogenic cascades induced by impaired cerebral glucose metabolism could result in neuronal degeneration and consequently cognitive deficits in AD patients. Among these pathogenic processes, altered functional status of thiamine metabolism and brain insulin resistance are highly emphasized and characterized as major pathogenic mechanisms. Finally, considering the fact that AD patients exhibit cerebral glucose hypometabolism possibly due to impairments of insulin signaling and altered thiamine metabolism, we also discuss some potential possibilities to uncover diagnostic biomarkers for AD from abnormal glucose metabolism and to develop drugs targeting at repairing insulin signaling impairment and correcting thiamine metabolism abnormality. We conclude that glucose metabolism abnormality plays a critical role in AD pathophysiological alterations through the induction of multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, and so forth. To clarify the causes, pathogeneses and consequences of cerebral hypometabolism in AD will help break the bottleneck of current AD study in finding ideal diagnostic biomarker and disease-modifying therapy. SN - 1873-5118 UR - https://www.unboundmedicine.com/medline/citation/23850509/Decoding_Alzheimer's_disease_from_perturbed_cerebral_glucose_metabolism:_implications_for_diagnostic_and_therapeutic_strategies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0301-0082(13)00053-1 DB - PRIME DP - Unbound Medicine ER -