茹宝根,张永海

缺氧是阿尔茨海默病（AD）的重要危险因素，缺氧及缺氧引起的氧化应激和线粒体功能障碍会加重脑内β-淀粉样蛋白沉积和Tau蛋白过度磷酸化，同时AD病理损伤也会导致脑组织葡萄糖和氧气供应减少，形成恶性循环，加重AD的进展。脑氧代谢率（CMRO2）是评估大脑氧稳态和代谢的重要指标，可能成为筛查、诊断AD的新型生物标志物。本文就近年来AD脑氧代谢异常的分子机制、AD氧代谢发生改变的脑区以及测定脑氧代谢的磁共振技术进行综述。

阿尔茨海默病；脑氧代谢；线粒体；缺氧；影像学技术

[1] 2023 Alzheimer's disease facts and figures[J].Alzheimers Dement,2023,19(4):1598-695. [2] ROBB W H,KHAN O A,AHMED H A,et al.Lower cerebral oxygen utilization is associated with Alzheimer's disease-related neurodegeneration and poorer cognitive performance among apolipoprotein Eε4 carriers[J].J Cereb Blood Flow Metab,2022,42(4):642-55. [3] HAI Y,REN K,ZHANG Y,et al.HIF-1αserves as a co-linker between AD and T2DM[J].Biomed Pharmacother,2024,171:116158. [4] ALEXANDER C,LI T,HATTORI Y,et al.Hypoxia Inducible Factor-1αbinds and activatesγ-secretase for Aβproduction under hypoxia and cerebral hypoperfusion[J].Mol Psychiatry,2022,27(10):4264-73. [5] YUAN M,FENG Y,ZHAO M,et al.Identification and verification of genes associated with hypoxia microenvironment in Alzheimer's disease[J].Sci Rep,2023,13(1):16252. [6] PENA E,SAN MARTIN-SALAMANCA R,EL ALAM S,et al.Tau Protein Alterations Induced by Hypobaric Hypoxia Exposure[J].Int J Mol Sci,2024,25(2). [7] JUNG E,KIM Y E,JEON H S,et al.Chronic hypoxia of endothelial cells boosts HIF-1α-NLRP1 circuit in Alzheimer's disease[J].Free Radic Biol Med,2023,204:385-93. [8] NORTLEY R,KORTE N,IZQUIERDO P,et al.Amyloidβoligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes[J].Science,2019,365(6450). [9] PAGANI L,ECKERT A.Amyloid-Beta interaction with mitochondria[J].Int J Alzheimers Dis,2011,2011:925050. [10] CARVALHO C,MOREIRA P I.Metabolic defects shared by Alzheimer's disease and diabetes:A focus on mitochondria[J].Curr Opin Neurobiol,2023,79:102694. [11] ESTERAS N,KUNDEL F,AMODEO G F,et al.Insoluble tau aggregates induce neuronal death through modification of membrane ion conductance,activation of voltage-gated calcium channels and NADPH oxidase[J].Febs j,2021,288(1):127-41. [12] ALQAHTANI T,DEORE S L,KIDE A A,et al.Mitochondrial dysfunction and oxidative stress in Alzheimer's disease,and Parkinson's disease,Huntington's disease and Amyotrophic Lateral Sclerosis-An updated review[J].Mitochondrion,2023,71:83-92. [13] TERADA T,OBI T,BUNAI T,et al.In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease[J]. Neurology,2020,94(15):e1592-e604. [14] MAYBLYUM D V,BECKER J A,JACOBS H I L,et al.Comparing PET and MRI Biomarkers Predicting Cognitive Decline in Preclinical Alzheimer Disease[J].Neurology,2021,96(24):e2933-e43. [15] ABDELMAKSOUD N M,SALLAM A M,ABULSOUD A I,et al.Unraveling the role of miRNAs in the diagnosis,progression,and therapeutic intervention of Alzheimer's disease[J].Pathol Res Pract,2024,253:155007. [16] BHATTI J S,KAUR S,MISHRA J,et al.Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease[J].Biochim Biophys Acta Mol Basis Dis,2023,1869(7):166798. [17] ZHANG H,WANG Y,LYU D,et al.Cerebral blood flow in mild cognitive impairment and Alzheimer's disease:A systematic review and meta-analysis[J].Ageing Res Rev,2021,71:101450. [18] TOHGI H,YONEZAWA H,TAKAHASHI S,et al.Cerebral blood flow and oxygen metabolism in senile dementia of Alzheimer's type and vascular dementia with deep white matter changes[J].Neuroradiology,1998,40(3):131-7. [19] NAGATA K,SATO M,SATOH Y,et al.Hemodynamic aspects of Alzheimer's disease[J].Ann N Y Acad Sci,2002,977:391-402. [20] CHIANG G C,CHO J,DYKE J,et al.Brain oxygen extraction and neural tissue susceptibility are associated with cognitive impairment in older individuals[J].J Neuroimaging,2022,32(4):697-709. [21] THOMAS B P,SHENG M,TSENG B Y,et al.Reduced global brain metabolism but maintained vascular function in amnestic mild cognitive impairment[J].J Cereb Blood Flow Metab,2017,37(4):1508-16. [22] JIANG D,LIN Z,LIU P,et al.Brain Oxygen Extraction Is Differentially Altered by Alzheimer's and Vascular Diseases[J].J Magn Reson Imaging,2020,52(6):1829-37. [23] LAJOIE I,NUGENT S,DEBACKER C,et al.Application of calibrated fMRI in Alzheimer's disease[J].Neuroimage Clin,2017,15:348-58. [24] YANG A,ZHUANG H,DU L,et al.Evaluation of whole-brain oxygen metabolism in Alzheimer's disease using QSM and quantitative BOLD[J].Neuroimage,2023,282:120381. [25] T A R,K K,PAUL J S.Unveiling metabolic patterns in dementia:Insights from high-resolution quantitative blood-oxygenation- level-dependent MRI[J].Med Phys,2024. [26] BIONDETTI E,CHO J,LEE H.Cerebral oxygen metabolism from MRI susceptibility[J].Neuroimage,2023,276:120189. [27] BOLAR D S,ROSEN B R,SORENSEN A G,et al.QUantitative Imaging of eXtraction of oxygen and TIssue consumption (QUIXOTIC)using venular-targeted velocity-selective spin labeling[J].Magn Reson Med,2011,66(6):1550-62. [28] DAVIS T L,KWONG K K,WEISSKOFF R M,et al.Calibrated functional MRI:mapping the dynamics of oxidative metabolism[J].Proc Natl Acad Sci U S A,1998,95(4):1834-9. [29] CHIARELLI P A,BULTE D P,WISE R,et al.A calibration method for quantitative BOLD fMRI based on hyperoxia[J].Neuroimage, 2007,37(3):808-20. [30] JIANG D,LU H.Cerebral oxygen extraction fraction MRI:Techniques and applications[J].Magn Reson Med,2022,88(2):575-600. [31] STONE A J,HOLLAND N C,BERMAN A J L,et al.Simulations of the effect of diffusion on asymmetric spin echo based quantitative BOLD:An investigation of the origin of deoxygenated blood volume overestimation[J].Neuroimage,2019,201:116035. [32] YIN Y,ZHANG Y,GAO J H.Dynamic measurement of oxygen extraction fraction using a multiecho asymmetric spin echo(MASE)pulse sequence[J].Magn Reson Med,2018,80(3):1118-24. [33] STONE A J,BLOCKLEY N P.A streamlined acquisition for mapping baseline brain oxygenation using quantitative BOLD[J].Neuroimage,2017,147:79-88. [34] LI H,WANG C,YU X,et al.Measurement of Cerebral Oxygen Extraction Fraction Using Quantitative BOLD Approach:A Review[J].Phenomics,2023,3(1):101-18. [35] KUDO K,LIU T,MURAKAMI T,et al.Oxygen extraction fraction measurement using quantitative susceptibility mapping:Comparison with positron emission tomography[J].J Cereb Blood Flow Metab,2016,36(8):1424-33. [36] CHO J,SPINCEMAILLE P,NGUYEN T D,et al.Temporal clustering,tissue composition,and total variation for mapping oxygen extraction fraction using QSM and quantitative BOLD[J].Magn Reson Med,2021,86(5):2635-46. [37] CHO J,LEE J,AN H,et al.Cerebral oxygen extraction fraction(OEF):Comparison of challenge-free gradient echo QSM+qBOLD (QQ)with(15)O PET in healthy adults[J].J Cereb Blood Flow Metab,2021,41(7):1658-68. [38] CHO J,ZHANG J,SPINCEMAILLE P,et al.QQ-NET-using deep learning to solve quantitative susceptibility mapping and quantitative blood oxygen level dependent magnitude(QSM+qBOLD or QQ)based oxygen extraction fraction(OEF)mapping[J].Magn Reson Med,2022,87(3):1583-94.

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