阿尔茨海默病的早期诊断研究进展
摘要
阿尔茨海默病是发病率较高且受到广泛重视的神经变性病,其发病机制尚未阐明,主要与β-淀粉样蛋白沉积、tau蛋白过度磷酸化、胆碱能神经元缺失有关。阿尔茨海默病的治疗以对症治疗为主,且无法逆转病程,因此早期诊断尤为重要。本文拟对近年阿尔茨海默病早期诊断研究进展进行综述,从神经生理学评估,生物标志物检测,影像学检查等几个方面对早期阿尔茨海默病进行评估,为早期诊断与有效治疗提供参考。
引文
[1]Suo W Z,Li L.Dysfunction of G protein-coupled receptor kinases in Alzheimer's disease[J].Thescientificworldjournal,2010,10:1667-1678.
[2]Hanger D P,Anderton B H,Noble W.Tau phosphorylation:the therapeutic challenge for neurodegenerative disease.Trends Mol Med[J].Trends in Molecular Medicine,2009,15(3):112-119.
[3]周丽华,徐武华.Tau蛋白相关标志物对阿尔茨海默病的诊断价值[J].实用老年医学,2017,31(3):285-287.
[4]Ittner A,Chua SW,Bertz J,et al.Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer's mice[J].Science,2016,354(6314):904-908.
[5]Podlesniy P,Llorens F,Golanska E,et al.Mitochondrial DNA differentiates Alzheimers disease from Creutzfeldt Jakob disease[J].Alzheimers Dement,2016,12(5):546-555.
[6]Yang Y,Yang XF,Wang YP,et al.Inhibition of protein phosphatases induces transport deficits and axonopathy[J].J Neurochem,2007,102(3):878-886.
[7]Llewellyn D J,Lang I A,Langa K M,et al.Vitamin D and Risk of Cognitive Decline in Elderly Persons[J].Archives of Internal Medicine,2010,170(13):1135-1141.
[8]Del S T,Steinwachs K C,Gertz H J,et al.Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib:a pilot study[J].Journal of Alzheimers Disease Jad,2013,33(1):205-215.
[9]Areagomez E,Schon E A.On the Pathogenesis of Alzheimer's Disease:The MAM Hypothesis[J].Faseb Journal Official Publication of the Federation of American Societies for Experimental Biology,2017,31(3):864-867.
[10]Karch CM,Goate AM.Alzheimers disease risk genes and mechanisms of disease pathogenesis[J].Biol Psychiatry,2015,77(1):43-51.
[11]Carrasquillo MM,Belbin O,Hunter TA,et al.Replication of CLU,CR1,and PICALM associations with Alzheimer disease[J].Arch Neurol,2010,67(8):961-964.
[12]Chou PS,Wu MN,Chou MC,et al.Angiotensin-converting enzyme insertion/deletion polymorphism and the longitudinal progression of Alzheimer's insertion disease[J].Geriatr Gerontol Int,2017,17(10):1544-1550.
[13]Reddy PH,Tonk S,Kumar SA,et al.A critical evaluation of neuroprotective and neurodegenerative MicroRNAs in Alzheimer's disease[J].Biochem Biophys Res Commun,2017,483(4):1156-1165.
[14]李国辉.载脂蛋白E4基因型预测老年缺血性脑血管病复发的意义[J].中国老年学杂志,2015,35(6):1594-1596.
[15]王美琴,杨铠冰,张敏.阿尔茨海默病的基因组学研究进展[J].中国康复理论与实践,2015,21(12):1365-1369.
[16]Thal DM,Sun B,Feng D,et al.Crystal structures of the M1 and M4 muscarinic acetylcholine receptors[J].Nature,2016,531(7594):335-340.
[17]孔欣,禹文峰,官志忠.激活星形胶质细胞α7乙酰胆碱能受体抑制β-淀粉样蛋白的聚集[J].中国老年学杂志,2016,36(13):3112-3115.
[18]Tang JX,Baranov D,Hammond M,et al.Human Alzheimer and inflammation biomarkers after anesthesia and surgery[J].Anesthesiology,2011,115(4):727-732.
[19]Ferretti MT,Bruno MA,Klein WL,et al.Intracellular Aβ-oligomers and early inflammation a model of Alzheimer's disease[J].Neurobiology of aging,2012,33(7):1329-1342.
[20]Unal A,Yiiter R,Yesil Y,et al.Is increased red cell distribution width(RDW)indicating the inflammation in Alzheimer's disease(AD)[J].Archives of gerontology and geriatrics,2013,56(1):50-54.
[21]Henu R,Combarros O,Breteler M,et al.Interactions between PPAR-αand inflammation related cytokine genes on the development of Alzheimer's disease,observed by the Epistasis Project[J].International journal of molecular epidemiology and genetics,2012,3(1):39-47.
[22]Mohsenzadegan M,Mirshafiey A.The immunopathogenic role of reactive oxygen species in Alzheimer disease[J].Iran J Allergy Asthma Immunol,2012,11(3):203-216.
[23]Cristov o J S,Santos R,Gomes C M.Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer's Disease[J].Oxidative Medicine and Cellular Longevity,2016(1):1-13.
[24]Greenough MA,Camakaris J,Bush AI.Metal dyshomeostasis and oxidative stress in Alzheimers disease[J].Neurochem Int,2013,62(5):540-555.
[25]Pedersen JT,Ostergaard J,Rozlosnik N,et al.Cu(II)mediates kinetically distinct,nonamyloid ogenic aggregation of amyloid-beta peptides[J].J Biol Chem,2011,286(30):26952-26963.
[26]Brawek B,Garaschuk O.Network-wide dysregulation of calcium homeostasis in Alzheimer's disease[J].Cell and Tissue Research,2014,357(2):427-438.
[27]陈茜茜,苏涛.微循环在阿尔茨海默病发生发展中的作用[J].生物化学与生物物理进展,2015,41(12):1077-1083.
[28]Fernandez-Vizarra P,Lopez-Franco O,Mallavia B,et al.Immunoglobulin GFc receptor deficiency prevents Alzheimer-like pathology and cognitive impairment inmice[J].Brain,2012,135(9):2826-2837.
[29]张景燕,王蓉,赵静姝,等.APP5肽类似P165和罗格列酮对SH-SY5Y细胞IRS-1和p-CREB表达的影响[J].首都医科大学学报,2011,32(4):484-488.
[30]张龙,王春梅.胰岛素及其受体和信号传导通路与阿尔兹海默病的研究进展[J].广东医学院学报,2013,31(1):75-77.
[31]Hong S,Beja-Glasser VF,Nfonoyim BM,et al.Complement and microglia mediate early synapse loss in Alzheimer mouse models[J].Science,2016,352(6286):712-716.
[32]Mc Khann GM,Knopman DS,Chertkow H,等.美国国立老化研究所与阿尔茨海默病协会诊断指南写作组:阿尔茨海默病源性轻度认知障碍诊断标准推荐[J].中华神经科杂志,2012,45(5):345-351.
[33]高中宝,王炜,赵杏丽,等.老年轻度认知功能损害患者认知水平的随访研究[J].中华医学杂志,2011,91(1):37-39.
[34]高明月,杨珉,况伟宏,等.简易精神状态量表得分的影响因素和正常值的筛查效度评价[J].北京大学学报:医学版,2015,3(3):443-449.
[35]刘桂芳,冯亚青,刘卫刚.认知功能筛查量表对阿尔茨海默病的诊断意义[J].中华老年心脑血管病杂志,2007,9(5):301-303.
[36]Mattsson N,Portelius E,Rolstad S,et al.Longitudinalcerebrospinal fluid biomarkers over four years in mild cognitive impairment[J].Alzheimer's Dis,2012,30(4):767-778.
[37]Yang L B,Lindholm K,Yan R,et al.Elevated betasecretase expression and enzymatic activity detected in sporadic Alzheimer disease[J].Nat Med,2003,9(1):3-4.
[38]Zhong Z,Ewers M,Teipel S,et al.Levels of betasecretase(BACE1)in cerebrospinal fluid as a predictor of risk in mild cognitive impairment[J].Archives of General Psychiatry,2007,64(6):718.
[39]Cheng X,He P,Lee T,et al.High activities of BACE1in brains with mild cognitive impairment[J].American Journal of Pathology,2014,184(1):141-7.
[40]Jiang H,Hampel H,Prvulovic D,et al.Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease[J].Molecular Neurodegeneration,2011,6(1):69.
[41]Wang R,Ji ZJ,Sheng SL,et al.Detection of urine neural thread protein for diagnosis of Alzheimer disease and its clinical significance[J].Chin J Lab Med,2010,33(1):46-50.
[42]Fagan A M,Holtzman D M.Cerebrospinal fluid biomarks of Alzheimer's disease[J].Biomarker Med,2010,4(1):51-63.
[43]Xiaojing,Jianjun,Xifei,et al.Cerebrospinal fluid biomarkers of Alzheimer's disease[J].科学通报(英文版),2014(2):233-242.
[44]Sun Y,Rong X,Lu W,et al.Translational study of Alzheimer's disease biomarkers from brain tissues in AβPP/PS1 mice and serum of AD patients[J].J Alzheimers Dis,2015,45(1):269-282.
[45]闫鹏,王蓉,杜怡峰,等.老年性痴呆患者尿中AD7cNTP含量的研究[J].山东大学学报医学版,2009,47(6):106-117.
[46]Okonkwo OC,Xu G,Dowling NM,et al.Family history of Alzheimer disease predicts hippoca-mpal atrophy in healthy middle-aged adults[J].Neurology,2012,78(22):1769-1 776.
[47]Frisoni GB.PET and ligands in the diagnosis of Alzheimer's disease[J].Lancet Neurology,2011,10(5):397-399.
[48]Lina M,Juan C,Rong W,et al.The level of Alzheimer-associated neuronal thread protein in urine may be an important biomarker of mild cognitive impairment[J].Journal of Clinical Neuroscience Official Journal of the Neurosurgical Society of Australasia,2015,22(4):649.
[49]Ma L,Chen J,Wang R,et al.Alzheimer-associated urine neuronal thread protein level increases with age in a healthy Chinese population[J].Journal of Clinical Neuroscience,2014,21(12):2118-2121.
[50]Wang,Zang,Liang,et al.Changes in hippocampal connectivity in the early stages of Alzheimer's disease:evidence from resting state f MRI[J].Neuro Image,2006,31(2):496.
[51]Johnson D K,Barrow W,Anderson R A,et al.Diagnostic Utility of Cerebral White Matter Integrity in Early Alzheimer's Disease[J].International Journal of Neuroscience,2010,120(8):544-550.
[52]Buizza L,Cenini G,Lanni C,et al.Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease[J].Plos One,2012,7(1):e29789.
[53]Diaz A,Rojas K,Espinosa B,et al.Aminoguanidine treatment ameliorates inflammatory responses and memory impairment induced by amyloid-beta 25-35 injection in rats[J].Neuropeptides,2014,48(3):153-159.
[54]Singh-Manoux A,Czernichow S,Elbaz A,et al.Obesity phenotypes in midlife and cognition in early old age.The Whitehall II cohort study[J].British Dental Journal,2012,213(11):755-762.
[2]Hanger D P,Anderton B H,Noble W.Tau phosphorylation:the therapeutic challenge for neurodegenerative disease.Trends Mol Med[J].Trends in Molecular Medicine,2009,15(3):112-119.
[3]周丽华,徐武华.Tau蛋白相关标志物对阿尔茨海默病的诊断价值[J].实用老年医学,2017,31(3):285-287.
[4]Ittner A,Chua SW,Bertz J,et al.Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer's mice[J].Science,2016,354(6314):904-908.
[5]Podlesniy P,Llorens F,Golanska E,et al.Mitochondrial DNA differentiates Alzheimers disease from Creutzfeldt Jakob disease[J].Alzheimers Dement,2016,12(5):546-555.
[6]Yang Y,Yang XF,Wang YP,et al.Inhibition of protein phosphatases induces transport deficits and axonopathy[J].J Neurochem,2007,102(3):878-886.
[7]Llewellyn D J,Lang I A,Langa K M,et al.Vitamin D and Risk of Cognitive Decline in Elderly Persons[J].Archives of Internal Medicine,2010,170(13):1135-1141.
[8]Del S T,Steinwachs K C,Gertz H J,et al.Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib:a pilot study[J].Journal of Alzheimers Disease Jad,2013,33(1):205-215.
[9]Areagomez E,Schon E A.On the Pathogenesis of Alzheimer's Disease:The MAM Hypothesis[J].Faseb Journal Official Publication of the Federation of American Societies for Experimental Biology,2017,31(3):864-867.
[10]Karch CM,Goate AM.Alzheimers disease risk genes and mechanisms of disease pathogenesis[J].Biol Psychiatry,2015,77(1):43-51.
[11]Carrasquillo MM,Belbin O,Hunter TA,et al.Replication of CLU,CR1,and PICALM associations with Alzheimer disease[J].Arch Neurol,2010,67(8):961-964.
[12]Chou PS,Wu MN,Chou MC,et al.Angiotensin-converting enzyme insertion/deletion polymorphism and the longitudinal progression of Alzheimer's insertion disease[J].Geriatr Gerontol Int,2017,17(10):1544-1550.
[13]Reddy PH,Tonk S,Kumar SA,et al.A critical evaluation of neuroprotective and neurodegenerative MicroRNAs in Alzheimer's disease[J].Biochem Biophys Res Commun,2017,483(4):1156-1165.
[14]李国辉.载脂蛋白E4基因型预测老年缺血性脑血管病复发的意义[J].中国老年学杂志,2015,35(6):1594-1596.
[15]王美琴,杨铠冰,张敏.阿尔茨海默病的基因组学研究进展[J].中国康复理论与实践,2015,21(12):1365-1369.
[16]Thal DM,Sun B,Feng D,et al.Crystal structures of the M1 and M4 muscarinic acetylcholine receptors[J].Nature,2016,531(7594):335-340.
[17]孔欣,禹文峰,官志忠.激活星形胶质细胞α7乙酰胆碱能受体抑制β-淀粉样蛋白的聚集[J].中国老年学杂志,2016,36(13):3112-3115.
[18]Tang JX,Baranov D,Hammond M,et al.Human Alzheimer and inflammation biomarkers after anesthesia and surgery[J].Anesthesiology,2011,115(4):727-732.
[19]Ferretti MT,Bruno MA,Klein WL,et al.Intracellular Aβ-oligomers and early inflammation a model of Alzheimer's disease[J].Neurobiology of aging,2012,33(7):1329-1342.
[20]Unal A,Yiiter R,Yesil Y,et al.Is increased red cell distribution width(RDW)indicating the inflammation in Alzheimer's disease(AD)[J].Archives of gerontology and geriatrics,2013,56(1):50-54.
[21]Henu R,Combarros O,Breteler M,et al.Interactions between PPAR-αand inflammation related cytokine genes on the development of Alzheimer's disease,observed by the Epistasis Project[J].International journal of molecular epidemiology and genetics,2012,3(1):39-47.
[22]Mohsenzadegan M,Mirshafiey A.The immunopathogenic role of reactive oxygen species in Alzheimer disease[J].Iran J Allergy Asthma Immunol,2012,11(3):203-216.
[23]Cristov o J S,Santos R,Gomes C M.Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer's Disease[J].Oxidative Medicine and Cellular Longevity,2016(1):1-13.
[24]Greenough MA,Camakaris J,Bush AI.Metal dyshomeostasis and oxidative stress in Alzheimers disease[J].Neurochem Int,2013,62(5):540-555.
[25]Pedersen JT,Ostergaard J,Rozlosnik N,et al.Cu(II)mediates kinetically distinct,nonamyloid ogenic aggregation of amyloid-beta peptides[J].J Biol Chem,2011,286(30):26952-26963.
[26]Brawek B,Garaschuk O.Network-wide dysregulation of calcium homeostasis in Alzheimer's disease[J].Cell and Tissue Research,2014,357(2):427-438.
[27]陈茜茜,苏涛.微循环在阿尔茨海默病发生发展中的作用[J].生物化学与生物物理进展,2015,41(12):1077-1083.
[28]Fernandez-Vizarra P,Lopez-Franco O,Mallavia B,et al.Immunoglobulin GFc receptor deficiency prevents Alzheimer-like pathology and cognitive impairment inmice[J].Brain,2012,135(9):2826-2837.
[29]张景燕,王蓉,赵静姝,等.APP5肽类似P165和罗格列酮对SH-SY5Y细胞IRS-1和p-CREB表达的影响[J].首都医科大学学报,2011,32(4):484-488.
[30]张龙,王春梅.胰岛素及其受体和信号传导通路与阿尔兹海默病的研究进展[J].广东医学院学报,2013,31(1):75-77.
[31]Hong S,Beja-Glasser VF,Nfonoyim BM,et al.Complement and microglia mediate early synapse loss in Alzheimer mouse models[J].Science,2016,352(6286):712-716.
[32]Mc Khann GM,Knopman DS,Chertkow H,等.美国国立老化研究所与阿尔茨海默病协会诊断指南写作组:阿尔茨海默病源性轻度认知障碍诊断标准推荐[J].中华神经科杂志,2012,45(5):345-351.
[33]高中宝,王炜,赵杏丽,等.老年轻度认知功能损害患者认知水平的随访研究[J].中华医学杂志,2011,91(1):37-39.
[34]高明月,杨珉,况伟宏,等.简易精神状态量表得分的影响因素和正常值的筛查效度评价[J].北京大学学报:医学版,2015,3(3):443-449.
[35]刘桂芳,冯亚青,刘卫刚.认知功能筛查量表对阿尔茨海默病的诊断意义[J].中华老年心脑血管病杂志,2007,9(5):301-303.
[36]Mattsson N,Portelius E,Rolstad S,et al.Longitudinalcerebrospinal fluid biomarkers over four years in mild cognitive impairment[J].Alzheimer's Dis,2012,30(4):767-778.
[37]Yang L B,Lindholm K,Yan R,et al.Elevated betasecretase expression and enzymatic activity detected in sporadic Alzheimer disease[J].Nat Med,2003,9(1):3-4.
[38]Zhong Z,Ewers M,Teipel S,et al.Levels of betasecretase(BACE1)in cerebrospinal fluid as a predictor of risk in mild cognitive impairment[J].Archives of General Psychiatry,2007,64(6):718.
[39]Cheng X,He P,Lee T,et al.High activities of BACE1in brains with mild cognitive impairment[J].American Journal of Pathology,2014,184(1):141-7.
[40]Jiang H,Hampel H,Prvulovic D,et al.Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease[J].Molecular Neurodegeneration,2011,6(1):69.
[41]Wang R,Ji ZJ,Sheng SL,et al.Detection of urine neural thread protein for diagnosis of Alzheimer disease and its clinical significance[J].Chin J Lab Med,2010,33(1):46-50.
[42]Fagan A M,Holtzman D M.Cerebrospinal fluid biomarks of Alzheimer's disease[J].Biomarker Med,2010,4(1):51-63.
[43]Xiaojing,Jianjun,Xifei,et al.Cerebrospinal fluid biomarkers of Alzheimer's disease[J].科学通报(英文版),2014(2):233-242.
[44]Sun Y,Rong X,Lu W,et al.Translational study of Alzheimer's disease biomarkers from brain tissues in AβPP/PS1 mice and serum of AD patients[J].J Alzheimers Dis,2015,45(1):269-282.
[45]闫鹏,王蓉,杜怡峰,等.老年性痴呆患者尿中AD7cNTP含量的研究[J].山东大学学报医学版,2009,47(6):106-117.
[46]Okonkwo OC,Xu G,Dowling NM,et al.Family history of Alzheimer disease predicts hippoca-mpal atrophy in healthy middle-aged adults[J].Neurology,2012,78(22):1769-1 776.
[47]Frisoni GB.PET and ligands in the diagnosis of Alzheimer's disease[J].Lancet Neurology,2011,10(5):397-399.
[48]Lina M,Juan C,Rong W,et al.The level of Alzheimer-associated neuronal thread protein in urine may be an important biomarker of mild cognitive impairment[J].Journal of Clinical Neuroscience Official Journal of the Neurosurgical Society of Australasia,2015,22(4):649.
[49]Ma L,Chen J,Wang R,et al.Alzheimer-associated urine neuronal thread protein level increases with age in a healthy Chinese population[J].Journal of Clinical Neuroscience,2014,21(12):2118-2121.
[50]Wang,Zang,Liang,et al.Changes in hippocampal connectivity in the early stages of Alzheimer's disease:evidence from resting state f MRI[J].Neuro Image,2006,31(2):496.
[51]Johnson D K,Barrow W,Anderson R A,et al.Diagnostic Utility of Cerebral White Matter Integrity in Early Alzheimer's Disease[J].International Journal of Neuroscience,2010,120(8):544-550.
[52]Buizza L,Cenini G,Lanni C,et al.Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease[J].Plos One,2012,7(1):e29789.
[53]Diaz A,Rojas K,Espinosa B,et al.Aminoguanidine treatment ameliorates inflammatory responses and memory impairment induced by amyloid-beta 25-35 injection in rats[J].Neuropeptides,2014,48(3):153-159.
[54]Singh-Manoux A,Czernichow S,Elbaz A,et al.Obesity phenotypes in midlife and cognition in early old age.The Whitehall II cohort study[J].British Dental Journal,2012,213(11):755-762.