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Prog Neurobiol. 2013 Sep;108:21-43. doi: 10.1016/j.pneurobio.2013.06.004. Epub 2013 Jul 11.

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

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


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.


(11)C-Pittsbergh compound; (18)F-fluorodeoxyglucose; 8-OHG; 8-hydroxyguanosine; AD; AD neuroimaging initiative; ADNI; ADP; AGEs; APOE; APP; APP C-terminal fragments; APP-CTFs; ATP; Advanced glycation endproducts; Alzheimer's disease; Apoptosis; Autophagy; Aβ; BBB; CHEIs; CMRglu; CNS; COX; CSF; Cerebral hypometabolism; Excitotoxicity; FDG; G6PDH; GLP-1; GLUT; GSK-3; Glucagon-like peptide-1; Glycogen synthase kinase 3; IDE; IGF-1; IR; IR substrate-1; IRS-1; Insulin resistance; KGDHC; LTP; MAPK; MCI; MMSE; MR; Mitochondrial dysfunction; N-methyl-D-aspartic acid receptor; NFTs; NMDAR; NSAID; Oxidative stress; PDHC; PET; PI3K; PKM2; PPP; PS1; Peroxisome proliferator-activated receptors; PiB; Positron emission tomography; RAGE; ROS; STZ; T1DM; T2DM; TCA; TD; TDP; TDPase; TGF; TMP; TMPase; TPK; Tau; Thiamine; adenosine driphosphate; adenosine triphosphate; advanced glycation end products; amyloid precursor protein; apolipoprotein E; blood brain barrier; central nervous system; cerebral metabolic rate of glucose; cerebrospinal fluid; cholinesterase inhibitors; cytochrome c oxidase; glucagon-like peptide-1; glucose transporter; glucose-6-phosphate dehydrogenase; glycogen synthase kinase-3; insulin receptor; insulin-degrading enzyme; insulin-like growth factor-1; long term potentiation; mTOR; magnetic resonance; mild cognitive impairment; mitogen-activated protein kinase; neurofibrillary tangles; non-steroidal anti-inflammatory drug; pentose phosphate pathway; phosphatidylinositide 3-kinases; positron emission tomography; presenilin-1; pyruvate dehydrogenase complex; pyruvate kinase isozyme type M2; rCBF; rCMRGlu; reactive oxygen species; regional CMRGlu; regional cerebral blood flow; streptozotocin; the Mini-Mental State Examination; the mammalian target of rapamycin; the receptor of AGEs; thiamine deficiency; thiamine diphosphatase; thiamine diphosphate; thiamine monophosphatase; thiamine monophosphate; thiamine pyrophosphokinase; transformation growth factor; tricarboxylic acid; type 1 diabetes mellitus; type 2 diabetes mellitus; α-ketoglutarate dehydrogenase complex; β-amyloid; γ-PPAR; γ-peroxisome proliferator-actived receptor

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