卡巴拉汀治疗阿尔茨海默病的脑局部一致性研究
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摘要
目的通过局部一致性(regional homogeneity,ReHo)分析方法探究卡巴拉汀治疗阿尔茨海默病(Alzheimer's disease,AD)的脑功能影像机制。方法 9例轻中度AD患者给予卡巴拉汀治疗24周,治疗前后分别进行全面的神经心理测评和静息态功能磁共振扫描。并选取年龄、性别、受教育年限与之相匹配的健康对照组9例进行静息态功能磁共振扫描,比较卡巴拉汀治疗前后AD患者大脑ReHo值的变化。结果与治疗前比,AD患者治疗后,表现出简易智力状态检查量表评分增加(P<0.05),老年痴呆症评估量表-认知部分和日常生活活动能力评分降低(P<0.05);AD患者在左内侧额上回,左侧眶内额上回和右侧杏仁核表现出ReHo值减少(P<0.05);此外,老年痴呆症评估量表-认知部分得分变化与左侧眶内额上回ReHo值呈正相关。结论卡巴拉汀能够改善AD的认知功能,可能是通过与认知相关的内侧额上回和杏仁核的自发脑活动来实现的,相关脑区未来有望作为此类药物疗效监测的生物学标志物。
OBJECTIVE To investigate the therapeutic mechanism of rivastigmine related to brain function by regional homogeneity(ReHo) in Alzheimer's disease(AD) patients. METHODS Treatment with rivastigmine was performed in 9 mild and moderate AD patients for 24 weeks. Before and after the treatment, they received comprehensive neuropsychological assessments and resting-state functional magnetic resonance imaging respectively. Meanwhile, resting-state functional magnetic resonance imaging was conducted on the healthy control group including 9 healthy individuals with the same age, gender and education with the aforesaid 9 AD patients, in an attempt to compare the changes in brain ReHo among the AD patients before and after the treatment with rivastigmine. RESULTS Compared with before treatment, after treatment of AD patients had an increase in their mini-mental state examination scores(P<0.05), while a decrease in scores of AD assessment scale-cognitive section and activity of daily living scale(P<0.05). The AD patients showed ReHo values reduced in the medial part of the left superior frontal gyrus, the medial orbital part of the left superior frontal gyrus and the right amygdala(P<0.05). In addition, the changes in scores of AD assessment scale-cognitive section were positive correlated with the ReHo values of the medial orbital part of the left superior frontal gyrus. CONCLUSION These findings suggest that rivastigmine's able to improve cognitive abilities of AD patients which may be achieved by altering spontaneous cerebration of the medial part of the superior frontal gyrus and the amygdala. Relevant brain regions are likely to serve as the biomarker for monitoring therapeutic effects of this kind of drugs in the future.
OBJECTIVE To investigate the therapeutic mechanism of rivastigmine related to brain function by regional homogeneity(ReHo) in Alzheimer's disease(AD) patients. METHODS Treatment with rivastigmine was performed in 9 mild and moderate AD patients for 24 weeks. Before and after the treatment, they received comprehensive neuropsychological assessments and resting-state functional magnetic resonance imaging respectively. Meanwhile, resting-state functional magnetic resonance imaging was conducted on the healthy control group including 9 healthy individuals with the same age, gender and education with the aforesaid 9 AD patients, in an attempt to compare the changes in brain ReHo among the AD patients before and after the treatment with rivastigmine. RESULTS Compared with before treatment, after treatment of AD patients had an increase in their mini-mental state examination scores(P<0.05), while a decrease in scores of AD assessment scale-cognitive section and activity of daily living scale(P<0.05). The AD patients showed ReHo values reduced in the medial part of the left superior frontal gyrus, the medial orbital part of the left superior frontal gyrus and the right amygdala(P<0.05). In addition, the changes in scores of AD assessment scale-cognitive section were positive correlated with the ReHo values of the medial orbital part of the left superior frontal gyrus. CONCLUSION These findings suggest that rivastigmine's able to improve cognitive abilities of AD patients which may be achieved by altering spontaneous cerebration of the medial part of the superior frontal gyrus and the amygdala. Relevant brain regions are likely to serve as the biomarker for monitoring therapeutic effects of this kind of drugs in the future.
引文
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[14]POWER J D,BARNES K A,SNYDER A Z,et al.Spurious but systematic correlations in functional connectivity MRInetworks arise from subject motion[J].Neuroimage,2012,59(3):2142-2154.
[15]ASHBURNER J.A fast diffeomorphic image registration algorithm[J].Neuroimage,2007,38(1):95-113.
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[26]FELLOWS L K,FARAH M J.The role of ventromedial prefrontal cortex in decision making:judgment under uncertainty or judgment per se?[J].Cereb Cortex,2007,17(11):2669-2674.
[27]MOTZKIN J C,PHILIPPI C L,WOLF R C,et al.Ventromedial prefrontal cortex is critical for the regulation of amygdala activity in humans[J].Biol Psychiatry,2015,77(3):276-284.
[28]QUIRK G J,GARCIA R,GONZáLEZ-LIMA F.Prefrontal mechanisms in extinction of conditioned fear[J].Biol Psychiatry,2006,60(4):337-343.
[29]YOUNG L,BECHARA A,TRANEL D,et al.Damage to ventromedial prefrontal cortex impairs judgment of harmful intent[J].Neuron,2010,65(6):845-851.
[30]ZHANG P Y,XU Q,DAI J P,et al.Dysfunction of affective network in post ischemic stroke depression:a resting-state functional magnetic resonance imaging study[J].Biomed Res Int,2014:846830.
[31]PRICE J L,DREVETS W C.Neurocircuitry of mood disorders[J].Neuropsychopharmacology,2010,35(1):192-216.
[32]WADSWORTH L P,LORIUS N,DONOVAN N J,et al.Neuropsychiatric symptoms and global functional impairment along the Alzheimer’s continuum[J].Dement Geriatr Cogn Disord,2012,34(2):96-111.
[33]ZUBENKO G S,ZUBENKO W N,MCPHERSON S,et al.Acollaborative study of the emergence and clinical features of the major depressive syndrome of Alzheimer’s disease[J].Am J Psychiatry,2003,160(5):857-866.
[34]SHINOTOH H,FUKUSHI K,NAGATSUKA S,et al.The amygdala and Alzheimer’s disease:positron emission tomographic study of the cholinergic system[J].Ann N YAcad Sci,2003(985):411-419.
[35]MOHAMMADI S,HAGHIR H,FAZEL A R,et al.Analysis of amygdala nucleus in the rat brain:A review study[J].Electron Physician,2013,5(2):639-642.
[36]WRIGHT C I,DICKERSON B C,FECZKO E,et al.Afunctional magnetic resonance imaging study of amygdala responses to human faces in aging and mild Alzheimer’s disease[J].Biol Psychiatry,2007,62(12):1388-1395.
[37]WANG Z Q,ZHANG M,HAN Y,et al.Differentially disrupted functional connectivity of the subregions of the amygdala in Alzheimer’s disease[J].J Xray Sci Technol,2016,24(2):329-342.
[38]ADOLPHS R,TRANEL D,DAMASIO H,et al.Fear and the human amygdala[J].J Neurosci,1995,15(9):5879-5891.
[39]NADER K,SCHAFE G E,LE DOUX J E.Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval[J].Nature,2000,406(6797):722-726.
[40]FANSELOW M S,GALE G D.The amygdala,fear,and memory[J].Ann N Y Acad Sci,2003(985):125-134.
[41]WHALEN P J,SHIN L M,MCINERNEY S C,et al.Afunctional MRI study of human amygdala responses to facial expressions of fear versus anger[J].Emotion,2001,1(1):70-83.
[42]SUSLOW T,KONRAD C,KUGEL H,et al.Automatic mood-congruent amygdala responses to masked facial expressions in major depression[J].Biol Psychiatry,2010,67(2):155-160.
[43]WANG L H,LABAR K S,SMOSKI M,et al.Prefrontal mechanisms for executive control over emotional distraction are altered in major depression[J].Psychiatry Res,2008,163(2):143-155.
[44]ORTNER M,PASQUINI L,BARAT M,et al.Progressively disrupted intrinsic functional connectivity of basolateral amygdala in very early Alzheimer’s disease[J].Front Neurol,2016(7):132.
[45]PHILIPPI N,BOTZUNG A,NOBLET V,et al.Impaired emotional autobiographical memory associated with right amygdalar-hippocampal atrophy in Alzheimer’s disease patients[J].Front Aging Neurosci,2015(7):21.
[46]ZHANG J T,GUO Z W,LIU X Z,et al.Abnormal functional connectivity of the posterior cingulate cortex is associated with depressive symptoms in patients with Alzheimer’s disease[J].Neuropsychiatr Dis Treat,2017(13):2589-2598.
[47]OLIéE,GUILLAUME S,JAUSSENT I,et al.Higher psychological pain during a major depressive episode May be a factor of vulnerability to suicidal ideation and act[J].JAffect Disord,2010,120(1/3):226-230.
[48]REISCH T,SEIFRITZ E,ESPOSITO F,et al.An fMRI study on mental pain and suicidal behavior[J].J Affect Disord,2010,126(1/2):321-325.
[49]HERHOLZ K,WEISENBACH S,ZüNDORF G,et al.In vivo study of acetylcholine esterase in basal forebrain,amygdala,and cortex in mild to moderate Alzheimer disease[J].Neuroimage,2004,21(1):136-143.
[50]YAO H X,LIU Y,ZHOU B,et al.Decreased functional connectivity of the amygdala in Alzheimer’s disease revealed by resting-state fMRI[J].Eur J Radiol,2013,82(9):1531-1538.
[51]WANG S B,TUO X P,ZHANG W J,et al.Effect of aspirin on learning and memory abilities and expression of inflammatory cytokines in hippocampus of Alzheimer’s disease rats[J].Chin J Mult Organ Dis Elder(中华老年多器官疾病杂志),2017,16(4):293-297.
[2]DONG W,WANG S,CHEN X,et al.Research progress on the mechanism of resveratrol in the prevention and treatment of Alzheimer’s disease[J].Chin J Mod Appl Pharm(中国现代应用药学),2018,35(11):1745-1748.
[3]SPERLING R A,AISEN P S,BECKETT L A,et al.Toward defining the preclinical stages of Alzheimer’s disease:recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease[J].Alzheimers Dement,2011,7(3):280-292.
[4]TAN C C,YU J T,WANG H F,et al.Efficacy and safety of donepezil,galantamine,rivastigmine,and memantine for the treatment of Alzheimer’s disease:a systematic review and meta-analysis[J].J Alzheimer’s Dis,2014,41(2):615-631.
[5]GOLBABAEI S,VAHID A,HATAMI J,et al.Classification of Alzheimer’s disease and mild cognitive impairment:Machine learning applied to rs-fMRI brain graphs[C]//201623rd Iranian Conference on Biomedical Engineering and 20161st International Iranian Conference on Biomedical Engineering(ICBME).New York,USA:2016.
[6]KHAZAEE A,EBRAHIMZADEH A,BABAJANI-FEREMIA.Identifying patients with Alzheimer’s disease using resting-state fMRI and graph theory[J].Clin Neurophysiol,2015,126(11):2132-2141.
[7]ZANG Y F,JIANG T Z,LU Y L,et al.Regional homogeneity approach to fMRI data analysis[J].Neuroimage,2004,22(1):394-400.
[8]GOVINDARAJULU Z,KENDALL M,GIBBONS J D.Rank correlation methods[J].Technometrics,1992,34(1):108.
[9]KIVINIEMI V.Endogenous brain fluctuations and diagnostic imaging[J].Hum Brain Mapp,2008,29(7):810-817.
[10]BAI Y,WANG W X,XU J,et al.Altered resting-state regional homogeneity after 13 weeks of paliperidone injection treatment in schizophrenia patients[J].Psychiatry Res Neuroimaging,2016(258):37-43.
[11]LAI C H.Frontal regional homogeneity increased and temporal regional homogeneity decreased after duloxetine treatment[J].Eur Neuropsychopharmacol,2011,21(Suppl 3):S354.
[12]KONG X M,XU S X,SUN Y,et al.Electroconvulsive therapy changes the regional resting state function measured by regional homogeneity(ReHo)and amplitude of low frequency fluctuations(ALFF)in elderly major depressive disorder patients:An exploratory study[J].Psychiatry Res Neuroimaging,2017(264):13-21.
[13]YAN C G,ZANG Y F.DPARSF:A MATLAB toolbox for“pipeline”data analysis of resting-state fMRI[J].Front Syst Neurosci,2010(4):13.
[14]POWER J D,BARNES K A,SNYDER A Z,et al.Spurious but systematic correlations in functional connectivity MRInetworks arise from subject motion[J].Neuroimage,2012,59(3):2142-2154.
[15]ASHBURNER J.A fast diffeomorphic image registration algorithm[J].Neuroimage,2007,38(1):95-113.
[16]TZOURIO-MAZOYER N,LANDEAU B,PAPATHANASSIOUD,et al.Automated anatomical labeling of activations in SPMusing a macroscopic anatomical parcellation of the MNI MRIsingle-subject brain[J].Neuroimage,2002,15(1):273-289.
[17]ONOR M L,TREVISIOL M,AGUGLIA E.Rivastigmine in the treatment of Alzheimer’s disease:An update[J].Clin Interv Aging,2007,2(1):17-32.
[18]R?SLER M,ANAND R,CICIN-SAIN A,et al.Efficacy and safety of rivastigmine in patients with Alzheimer’s disease:international randomised controlled trial[J].BMJ,1999,318(7184):633-638.
[19]MATSUZONO K,SATO K,KONO S,et al.Clinical benefits of rivastigmine in the real world dementia clinics of the Okayama rivastigmine study(ORS)[J].J Alzheimers Dis,2015,48(3):757-763.
[20]WOO R S,LEE J H,YU H N,et al.Expression of ErbB4 in the neurons of Alzheimer’s disease brain and APP/PS1 mice,a model of Alzheimer’s disease[J].Anat Cell Biol,2011,44(2):116.
[21]DU BOISGUEHENEUC F,LEVY R,VOLLE E,et al.Functions of the left superior frontal gyrus in humans:a lesion study[J].Brain,2006,129(Pt 12):3315-3328.
[22]FUJIMOTO H,MATSUOKA T,KATO Y,et al.Brain regions associated with anosognosia for memory disturbance in Alzheimer’s disease:a magnetic resonance imaging study[J].Neuropsychiatr Dis Treat,2017(13):1753-1759.
[23]JIANG J H,SUN Y W,ZHOU H C,et al.Study of the influence of age in 18F-FDG PET images using a data-driven approach and its evaluation in alzheimer’s disease[J].Contrast Media Mol Imaging,2018:3786083.
[24]XU J,REES G,YIN X,et al.Spontaneous neuronal activity predicts intersubject variations in executive control of attention[J].Neuroscience,2014(263):181-192.
[25]SHIBATA K,NARUMOTO J,KITABAYASHI Y,et al.Correlation between anosognosia and regional cerebral blood flow in Alzheimer’s disease[J].Neurosci Lett,2008,435(1):7-10.
[26]FELLOWS L K,FARAH M J.The role of ventromedial prefrontal cortex in decision making:judgment under uncertainty or judgment per se?[J].Cereb Cortex,2007,17(11):2669-2674.
[27]MOTZKIN J C,PHILIPPI C L,WOLF R C,et al.Ventromedial prefrontal cortex is critical for the regulation of amygdala activity in humans[J].Biol Psychiatry,2015,77(3):276-284.
[28]QUIRK G J,GARCIA R,GONZáLEZ-LIMA F.Prefrontal mechanisms in extinction of conditioned fear[J].Biol Psychiatry,2006,60(4):337-343.
[29]YOUNG L,BECHARA A,TRANEL D,et al.Damage to ventromedial prefrontal cortex impairs judgment of harmful intent[J].Neuron,2010,65(6):845-851.
[30]ZHANG P Y,XU Q,DAI J P,et al.Dysfunction of affective network in post ischemic stroke depression:a resting-state functional magnetic resonance imaging study[J].Biomed Res Int,2014:846830.
[31]PRICE J L,DREVETS W C.Neurocircuitry of mood disorders[J].Neuropsychopharmacology,2010,35(1):192-216.
[32]WADSWORTH L P,LORIUS N,DONOVAN N J,et al.Neuropsychiatric symptoms and global functional impairment along the Alzheimer’s continuum[J].Dement Geriatr Cogn Disord,2012,34(2):96-111.
[33]ZUBENKO G S,ZUBENKO W N,MCPHERSON S,et al.Acollaborative study of the emergence and clinical features of the major depressive syndrome of Alzheimer’s disease[J].Am J Psychiatry,2003,160(5):857-866.
[34]SHINOTOH H,FUKUSHI K,NAGATSUKA S,et al.The amygdala and Alzheimer’s disease:positron emission tomographic study of the cholinergic system[J].Ann N YAcad Sci,2003(985):411-419.
[35]MOHAMMADI S,HAGHIR H,FAZEL A R,et al.Analysis of amygdala nucleus in the rat brain:A review study[J].Electron Physician,2013,5(2):639-642.
[36]WRIGHT C I,DICKERSON B C,FECZKO E,et al.Afunctional magnetic resonance imaging study of amygdala responses to human faces in aging and mild Alzheimer’s disease[J].Biol Psychiatry,2007,62(12):1388-1395.
[37]WANG Z Q,ZHANG M,HAN Y,et al.Differentially disrupted functional connectivity of the subregions of the amygdala in Alzheimer’s disease[J].J Xray Sci Technol,2016,24(2):329-342.
[38]ADOLPHS R,TRANEL D,DAMASIO H,et al.Fear and the human amygdala[J].J Neurosci,1995,15(9):5879-5891.
[39]NADER K,SCHAFE G E,LE DOUX J E.Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval[J].Nature,2000,406(6797):722-726.
[40]FANSELOW M S,GALE G D.The amygdala,fear,and memory[J].Ann N Y Acad Sci,2003(985):125-134.
[41]WHALEN P J,SHIN L M,MCINERNEY S C,et al.Afunctional MRI study of human amygdala responses to facial expressions of fear versus anger[J].Emotion,2001,1(1):70-83.
[42]SUSLOW T,KONRAD C,KUGEL H,et al.Automatic mood-congruent amygdala responses to masked facial expressions in major depression[J].Biol Psychiatry,2010,67(2):155-160.
[43]WANG L H,LABAR K S,SMOSKI M,et al.Prefrontal mechanisms for executive control over emotional distraction are altered in major depression[J].Psychiatry Res,2008,163(2):143-155.
[44]ORTNER M,PASQUINI L,BARAT M,et al.Progressively disrupted intrinsic functional connectivity of basolateral amygdala in very early Alzheimer’s disease[J].Front Neurol,2016(7):132.
[45]PHILIPPI N,BOTZUNG A,NOBLET V,et al.Impaired emotional autobiographical memory associated with right amygdalar-hippocampal atrophy in Alzheimer’s disease patients[J].Front Aging Neurosci,2015(7):21.
[46]ZHANG J T,GUO Z W,LIU X Z,et al.Abnormal functional connectivity of the posterior cingulate cortex is associated with depressive symptoms in patients with Alzheimer’s disease[J].Neuropsychiatr Dis Treat,2017(13):2589-2598.
[47]OLIéE,GUILLAUME S,JAUSSENT I,et al.Higher psychological pain during a major depressive episode May be a factor of vulnerability to suicidal ideation and act[J].JAffect Disord,2010,120(1/3):226-230.
[48]REISCH T,SEIFRITZ E,ESPOSITO F,et al.An fMRI study on mental pain and suicidal behavior[J].J Affect Disord,2010,126(1/2):321-325.
[49]HERHOLZ K,WEISENBACH S,ZüNDORF G,et al.In vivo study of acetylcholine esterase in basal forebrain,amygdala,and cortex in mild to moderate Alzheimer disease[J].Neuroimage,2004,21(1):136-143.
[50]YAO H X,LIU Y,ZHOU B,et al.Decreased functional connectivity of the amygdala in Alzheimer’s disease revealed by resting-state fMRI[J].Eur J Radiol,2013,82(9):1531-1538.
[51]WANG S B,TUO X P,ZHANG W J,et al.Effect of aspirin on learning and memory abilities and expression of inflammatory cytokines in hippocampus of Alzheimer’s disease rats[J].Chin J Mult Organ Dis Elder(中华老年多器官疾病杂志),2017,16(4):293-297.