ApoEε4等位基因与老年人术后认知功能障碍关系的基础与临床研究
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摘要
术后认知功能障碍(PostoPerative cognitive dysfuction,POCD)是指麻醉手术后病人记忆力、抽象思维、定向力障碍,同时伴有社会活动能力的减退,即人格、社交能力及认知能力和技巧的改变,是老年患者术后常见的中枢神经系统并发症。随着人口老龄化和手术麻醉技术的发展,将会有越来越多的老年人接受外科手术治疗,老年患者POCD的问题将会是一个日渐突出的问题。ApoE基因位于人第19号染色体的长臂,由三种常见的等位基因:ε2、ε3和ε4编码产生三种ApoE异构体E2、E3和E4。ApoE基因型及等位基因频率的分布有种族和性别差异。ApoEε4等位基因与老年性痴呆的关系研究较多,结果已经比较明确。ApoEε4是老年性痴呆的危险因素。ApoEε4等位基因很可能为POCD的危险因素之一。但目前ApoE基因在POCD发病中的作用研究较少,尤其缺乏较大样本的研究,因而至今没有一致的结果。
本研究对192例老年手术患者的载脂蛋白E(ApoE)等位基因分布进行分析,观察不同基因型的患者手术前后认知功能的变化差异,并比较各种基因型患者POCD发生率的差异,分析ApoEε4等位基因在POCD预测诊断中的意义。
1.方法
1.一般资料选择骨科股骨颈骨折行全髋人工关节置换术的病人192例,年龄75～89岁,平均(82±7)岁择期手术病,ASA分级Ⅰ～Ⅲ级。患者均来自2008年1月～2009年1月山东中医药大学附属医院,其中男94例,女98例。纳入标准:愿意和能够完成各种神经精神测试,排除肝性脑病、中风后遗症等神经和精神系统疾病。排除标准:不愿意或不能完成神经精神功能测试、术中或术后发生器官功能衰竭等病变需要抢救的患者;术后1周内有严重精神状态改变且影像学检查大脑有明显器质性改变者。
2.麻醉和监测建立有创挠动脉血压、心率和脉搏血氧饱和度监测,记录手术时间、术中失血量、术中低血压总时间、以及文化程度。麻醉方法病人选取患侧朝上侧卧位,腰2～3间隙行连续腰麻,头向置管,初始量推入1.2毫升0.75%的罗哌卡因,调节麻醉平面,两小时推入维持药量0.8毫升。
3.认知功能评价及POCD的诊断:使用神经、精神功能测试。于术前1天和术后1周采用韦氏成人智力量表(WAIS)和韦氏记忆量表(WMS)对患者进行神经、精神功能测试。测试包括9个项目:数字广度测试(顺向、逆向);累加测试;联想学习测试;视觉再生能力;数字符号测试;连线试验;钉板测验(利手、非利手)。POCD的诊断标准:以患者术后在9个测试项目中有多于20%的项目认知结果比术前下降20%以上为POCD的诊断标准。测定认知水平:用取Z值的方法将患者每一项测试的结果进行标准化转换,得到标准化值(Z值)。Z值=(该项目成绩-该项目均数)/该项目标准差,所有9项测试术前Z值的均数作为该患者术前的基础认知水平,同样方法求得术后7天标准化的认知水平。
1.4.2ApoE基因型检测根据Wenham等的经典聚合酶链反应限制性片段长度多态性(PCR-RFLP)方法,检测ApoE基因型,并计算出等位基因频率。上游引物5'-TCCAAGGAGCTGCAGGCGGCGCA-3'下游引物5'-ACAGAATTCGCCCCGGCCTGGTACACTGCCA-3'。
1.5计量资料以均数±标准差表示,发生率、ApoE基因型频率和等位基因频率分布以百分率(%)表示。统计学处理采用SPSS13.0软件包,组间计量资料比较采用立样本t检验,组间分类资料的比较用x~2检验或Fisher精确概率,相关性采用Logistic回归分析。P＜0.05认为有显著性差异。
2结果
2.1.ApoE基因型分布及其对老年人认知功能影响
192例患者的ApoE基因型的分布如下:ε2/ε2,2例(1%);ε2/ε3,26例(13.5%);ε3/ε3,141例(73.4%);ε2/ε4,4例(2.1%);ε3/ε4,18例(9.4%);ε4/ε4,1例(0.5%)。所有患者中携带有ε4基因的为23例(12.0%);不携带有ε4基因的169例(88.0%)。ε4的等位基因频率为6.25%。ε4基因携带组与ε4非携带组术前认知评分无统计学差异,术后7天,ε4基因携带组有5项指标较术前较明显下降(P＜0.01),ε4非携带组2项指标较术前下降。术后7天ε4基因携带组有三项认知指标低于ε4非携带组。ε4携带组和ε4非携带组年龄、性别、术中动脉血压、手术时间、术中失血量、术中低血压总时间、以及文化程度等无统计学差异。
2.2 ApoE基因型对POCD的诊断预测价值POCD患者和对照的ApoE基因型分布如表3所示。采用Logistic回归分析显示apoEε4等位基因是POCD发生的独立危险因素(odds ratio:3.89,95%CI:1.52～8.47)。ApoEε4等位基因携带者POCD的发生率为78.3%,显著高于ε4等位基因非携带者中POCD的发生率47.9%(P＜0.01)。
结论
1.显示ApoEε4基因型对术前老年人的认知水平没有明显影响,。
2.ε4等位基因携带者术后有多项认知指标低于非携带者
3.POCD患者ApoEε4等位基因频率显著高于非POCD病人。
4.携带ε4为POCD的独立危险因素。
Objective: To study the correlation between Cognitive Function, Postoperative Cognitive Dysfunction and the Apolipoproteinε4 Allele in the Elderly. Methods: Cognitive function was evaluated by WAIS and WMS tests before operation, at one week after operation. Apo E allele genotypes were detected by PCR-RFLP method. Results: The cognitive scores decreased more after operation in ApoEε4 carriers compared to non-carriers. The incidence of POCD was higher in Apo Eε4 carriers than that in the non-carrier (P<0.01). Conclusion: Apo Eε4 allele gene is a factor accounting for post operative cognitive impairing and an independent risk factor for postoperative cognitive dysfunction in the elderly.
本研究对192例老年手术患者的载脂蛋白E(ApoE)等位基因分布进行分析,观察不同基因型的患者手术前后认知功能的变化差异,并比较各种基因型患者POCD发生率的差异,分析ApoEε4等位基因在POCD预测诊断中的意义。
1.方法
1.一般资料选择骨科股骨颈骨折行全髋人工关节置换术的病人192例,年龄75～89岁,平均(82±7)岁择期手术病,ASA分级Ⅰ～Ⅲ级。患者均来自2008年1月～2009年1月山东中医药大学附属医院,其中男94例,女98例。纳入标准:愿意和能够完成各种神经精神测试,排除肝性脑病、中风后遗症等神经和精神系统疾病。排除标准:不愿意或不能完成神经精神功能测试、术中或术后发生器官功能衰竭等病变需要抢救的患者;术后1周内有严重精神状态改变且影像学检查大脑有明显器质性改变者。
2.麻醉和监测建立有创挠动脉血压、心率和脉搏血氧饱和度监测,记录手术时间、术中失血量、术中低血压总时间、以及文化程度。麻醉方法病人选取患侧朝上侧卧位,腰2～3间隙行连续腰麻,头向置管,初始量推入1.2毫升0.75%的罗哌卡因,调节麻醉平面,两小时推入维持药量0.8毫升。
3.认知功能评价及POCD的诊断:使用神经、精神功能测试。于术前1天和术后1周采用韦氏成人智力量表(WAIS)和韦氏记忆量表(WMS)对患者进行神经、精神功能测试。测试包括9个项目:数字广度测试(顺向、逆向);累加测试;联想学习测试;视觉再生能力;数字符号测试;连线试验;钉板测验(利手、非利手)。POCD的诊断标准:以患者术后在9个测试项目中有多于20%的项目认知结果比术前下降20%以上为POCD的诊断标准。测定认知水平:用取Z值的方法将患者每一项测试的结果进行标准化转换,得到标准化值(Z值)。Z值=(该项目成绩-该项目均数)/该项目标准差,所有9项测试术前Z值的均数作为该患者术前的基础认知水平,同样方法求得术后7天标准化的认知水平。
1.4.2ApoE基因型检测根据Wenham等的经典聚合酶链反应限制性片段长度多态性(PCR-RFLP)方法,检测ApoE基因型,并计算出等位基因频率。上游引物5'-TCCAAGGAGCTGCAGGCGGCGCA-3'下游引物5'-ACAGAATTCGCCCCGGCCTGGTACACTGCCA-3'。
1.5计量资料以均数±标准差表示,发生率、ApoE基因型频率和等位基因频率分布以百分率(%)表示。统计学处理采用SPSS13.0软件包,组间计量资料比较采用立样本t检验,组间分类资料的比较用x~2检验或Fisher精确概率,相关性采用Logistic回归分析。P＜0.05认为有显著性差异。
2结果
2.1.ApoE基因型分布及其对老年人认知功能影响
192例患者的ApoE基因型的分布如下:ε2/ε2,2例(1%);ε2/ε3,26例(13.5%);ε3/ε3,141例(73.4%);ε2/ε4,4例(2.1%);ε3/ε4,18例(9.4%);ε4/ε4,1例(0.5%)。所有患者中携带有ε4基因的为23例(12.0%);不携带有ε4基因的169例(88.0%)。ε4的等位基因频率为6.25%。ε4基因携带组与ε4非携带组术前认知评分无统计学差异,术后7天,ε4基因携带组有5项指标较术前较明显下降(P＜0.01),ε4非携带组2项指标较术前下降。术后7天ε4基因携带组有三项认知指标低于ε4非携带组。ε4携带组和ε4非携带组年龄、性别、术中动脉血压、手术时间、术中失血量、术中低血压总时间、以及文化程度等无统计学差异。
2.2 ApoE基因型对POCD的诊断预测价值POCD患者和对照的ApoE基因型分布如表3所示。采用Logistic回归分析显示apoEε4等位基因是POCD发生的独立危险因素(odds ratio:3.89,95%CI:1.52～8.47)。ApoEε4等位基因携带者POCD的发生率为78.3%,显著高于ε4等位基因非携带者中POCD的发生率47.9%(P＜0.01)。
结论
1.显示ApoEε4基因型对术前老年人的认知水平没有明显影响,。
2.ε4等位基因携带者术后有多项认知指标低于非携带者
3.POCD患者ApoEε4等位基因频率显著高于非POCD病人。
4.携带ε4为POCD的独立危险因素。
Objective: To study the correlation between Cognitive Function, Postoperative Cognitive Dysfunction and the Apolipoproteinε4 Allele in the Elderly. Methods: Cognitive function was evaluated by WAIS and WMS tests before operation, at one week after operation. Apo E allele genotypes were detected by PCR-RFLP method. Results: The cognitive scores decreased more after operation in ApoEε4 carriers compared to non-carriers. The incidence of POCD was higher in Apo Eε4 carriers than that in the non-carrier (P<0.01). Conclusion: Apo Eε4 allele gene is a factor accounting for post operative cognitive impairing and an independent risk factor for postoperative cognitive dysfunction in the elderly.
引文
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9.Ding,L.,et al.,[Effects of ketamine and splenectomy on cognition and synaptic plasticity in hippocampus of senile rats].Zhonghua Yi Xue Za Zhi,2009.89(17):p.1203-6.
10.Djaiani,G.N.,Aortic arch atheroma:stroke reduction in cardiac surgical patients.Semin Cardiothorac Vasc Anesth,2006.10(2):p.143-57.
11.Eljamel,M.S.,Ablative neurosurgery for mental disorders:is there still a role in the 21st century? A personal perspective.Neurosurg Focus,2008.25(1):p. E4.
12.Enlund,A.and M.Enlund,[Postoperative cognitive dysfunction can be connected to 1-year mortality.The role of anesthetics is not yet clear].Lakartidningen,2009.106(4):p.184-7.
13.Fesenko,U.A.,Piracetam improves children's memory after general anaesthesia.Anestezjol Intens Ter,2009.41(1):p.16-21.
14.Xie,Z.and R.E.Tanzi,Alzheimer's disease and post-operative cognitive dysfunction.Exp Gerontol,2006.41(4):p.346-59.
15.Pesonen,A.,et al.,Applicability of tools to assess pain in elderly patients after cardiac surgery.Acta Anaesthesiol Scand,2008.52(2):p.267-73.
16.Denheyer,M.,Z.H.Kiss,and A.M.Haffenden,Behavioral effects of subthalamic deep brain stimulation in Parkinson's disease.Neuropsychologia,2009.
17.Gottesman,R.F.and R.J.Wityk,Brain injury from cardiac bypass procedures.Semin Neurol,2006.26(4):p.432-9.
18.Steinmetz,J.and L.S.Rasmussen,Choice reaction time in patients with post-operative cognitive "dysfunction.Acta Anaesthesiol Stand,2008.52(1):p.95-8.
19.Barber,P.A.,et al.,Cerebral ischemic lesions on diffusion-weighted imaging are associated with neurocognitive decline after cardiac surgery.Stroke,2008.39(5):p.1427-33.
20.Halpern,C.H.,et al.,Cognition following bilateral deep brain stimulation surgery of the subthalamic nucleus for Parkinson's disease.Int J Geriatr Psychiatry,2009.24(5):p.443-51.
21.Battaglia,D.,et al.,Cognitive assessment in epilepsy surgery of children.Childs Nerv Syst,2006.22(8):p.744-59.
22.Carrascal,Y.,et al.,Cognitive decline after cardiac surgery:proposal for easy measurement with a new test.Interact Cardiovasc Thorac Surg,2005.4(3):p.216-21.
23.Steinmetz,J.and L.S.Rasmussen,[Cognitive deterioration after surgery]. Ugeskr Laeger,2008.170(49):p.4032-4.
24.Yoshitani,K.and Y.Ohnishi,[Cognitive dysfunction after cardiac surgery].Masui,2009.58(3):p.308-14.
25.Funder,K.S.,J.Steinmetz,and L.S.Rasmussen,Cognitive dysfunction after cardiovascular surgery.Minerva Anestesiol,2009.75(5):p.329-32.
26.Zhang,C.H.,et al.,[The effect of beating heart intracardiac procedures on postoperative cognitive function and SlOOb release:analysis of 51 patients].Zhonghua Yi Xue Za Zhi,2007.87(29):p.2054-7.
27.Soinne,L.,et al.,The effect of severe carotid occlusive disease and its surgical treatment on cognitive functions of the brain.Brain Cogn,2009.69(2):p.353-9.
28.Kalbe,E.,et al.,Frontal FDG-PET activity correlates with cognitive outcome after STN-DBS in Parkinson disease.Neurology,2009.72(1):p.42-9.
29.Gottesman,R.F.,et al.,Early postoperative cognitive dysfunction and blood pressure during coronary artery bypass graft operation.Arch Neurol,2007.64(8):p.1111-4.
30.Caza,N.,et al.,The effects of surgery and anesthesia on memory and cognition.Prog Brain Res,2008.169:p.409-22.
31.Smith,P.J.,et al.,Executive function and depression as independent risk factors for postoperative delirium.Anesthesiology,2009.110(4):p.781-7.
32.Diot,E.,et al.,[Favorable outcome of acute porphyric neuropathy after treatment with heme arginate].Rev Neurol(Paris),2007.163(11):p.1100-2.
33.Weber,C.F.,et al.,Impact of general versus local anesthesia on early postoperative cognitive dysfunction following carotid endarterectomy." GALA Study Subgroup Analysis.World J Surg,2009.33(7):p.1526-32.
34.Wei,J.L.,et al.,Improved behavior and sleep after adenotonsillectomy in children with sleep-disordered breathing.Arch Otolaryngol Head Neck Surg,2007.133(10):p.974-9.
35.Puskas,F.,et al.,Intraoperative hyperglycemia and cognitive decline after CABG.Ann Thorac Surg,2007.84(5):p.1467-73.
36.Xie,Z.,et al.,Isoflurane-induced apoptosis:a potential pathogenic link between delirium and dementia.J Gerontol A Biol Sci Med Sci,2006.61(12):p.1300-6.
37.Murkin,J.M.,Neurologic complications in noncardiac surgery.Semin Cardiothorac Vasc Anesth,2006.10(2):p.125-7.
38.Reichenberg,A.,et al.,Neuropsychiatric consequences of coronary artery bypass grafting and noncardiovascular surgery.Dialogues Clin Neurosci,2007.9(1):p.85-91.
39.Walker,M.D.,et al.,Neuropsychological features in primary hyperparathyroidism:a prospective study.J Clin Endocrinol Metab,2009.94(6):p.1951-8.
40.Paquot-Le Brun,C.,et al.,[Otologic sequels in velopalatine clefts.Analysis and management].Rev Stomatol Chir Maxillofac,2007.108(4):p.357-68.
41.Chiang,S.,et al.,Pharmacologic management of the older woman undergoing surgery.Womens Health(Lond Engl),2009.5(2):p.205-19.
42.Cook,D.J.,et al.,Postcardiac surgical cognitive impairment in the aged using diffusion-weighted magnetic resonance imaging.Ann Thorac Surg,2007.83(4):p.1389-95.
2.Bitsch,M.S.,et al.,Acute cognitive dysfunction after hip fracture." frequency and risk factors in an optimized,multimodal,rehabilitation program.Acta Anaesthesiol Scand,2006.50(4):p.428-36.
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1.Amiez,C.,et al.,Preoperative functional magnetic resonance imaging assessment of higher-order cognitive function in patients undergoing surgery for brain tumors.J Neurosurg,2008.105(2):p.258-68.
2.Aubrun,F.and F.Marmion,The elderly patient and postoperative pain treatment.Best Pract Res Clin Anaesthesiol,2007.21(1):p.109-27.
3.Baxendale,S.,The impact of epilepsy surgery on cognition and behavior.Epilepsy Behav,2008.12(4):p.592-9.
4.Molnar,T.,et al.,Increased levels of baseline biomarkers reflecting platelet and endothelial activation predict early cognitive dysfunction after lung surgery.Eur J Anaesthesiol,2009.26(8):p.708-10.
5.Castelli,L.,et al.,Does subthalamic stimulation induce personality modifications in Parkinson's disease? A Rorschach Test explorative study.Acta Neurol Belg,2008.1D8(1):p.5-8.
6.Dahl,V.and J.Raeder,Regional anaesthesia in ambulatory surgery.Curr Opin Anaesthesiol,2003.16(5):p.471-6.
7.de Ribaupierre,S.,et al.,Cerebellar lesions:is there a lateralisation effect on memory deficits? Acta Neurochir(Wien),2008.150(6):p.545-50;discussion 550.
8.Delmaire,C.,et al.,[Functional magnetic resonance imaging:physiopathology,techniques and applications].J Radiol,2007.88(3 Pt 2):p.497-509.
9.Ding,L.,et al.,[Effects of ketamine and splenectomy on cognition and synaptic plasticity in hippocampus of senile rats].Zhonghua Yi Xue Za Zhi,2009.89(17):p.1203-6.
10.Djaiani,G.N.,Aortic arch atheroma:stroke reduction in cardiac surgical patients.Semin Cardiothorac Vasc Anesth,2006.10(2):p.143-57.
11.Eljamel,M.S.,Ablative neurosurgery for mental disorders:is there still a role in the 21st century? A personal perspective.Neurosurg Focus,2008.25(1):p. E4.
12.Enlund,A.and M.Enlund,[Postoperative cognitive dysfunction can be connected to 1-year mortality.The role of anesthetics is not yet clear].Lakartidningen,2009.106(4):p.184-7.
13.Fesenko,U.A.,Piracetam improves children's memory after general anaesthesia.Anestezjol Intens Ter,2009.41(1):p.16-21.
14.Xie,Z.and R.E.Tanzi,Alzheimer's disease and post-operative cognitive dysfunction.Exp Gerontol,2006.41(4):p.346-59.
15.Pesonen,A.,et al.,Applicability of tools to assess pain in elderly patients after cardiac surgery.Acta Anaesthesiol Scand,2008.52(2):p.267-73.
16.Denheyer,M.,Z.H.Kiss,and A.M.Haffenden,Behavioral effects of subthalamic deep brain stimulation in Parkinson's disease.Neuropsychologia,2009.
17.Gottesman,R.F.and R.J.Wityk,Brain injury from cardiac bypass procedures.Semin Neurol,2006.26(4):p.432-9.
18.Steinmetz,J.and L.S.Rasmussen,Choice reaction time in patients with post-operative cognitive "dysfunction.Acta Anaesthesiol Stand,2008.52(1):p.95-8.
19.Barber,P.A.,et al.,Cerebral ischemic lesions on diffusion-weighted imaging are associated with neurocognitive decline after cardiac surgery.Stroke,2008.39(5):p.1427-33.
20.Halpern,C.H.,et al.,Cognition following bilateral deep brain stimulation surgery of the subthalamic nucleus for Parkinson's disease.Int J Geriatr Psychiatry,2009.24(5):p.443-51.
21.Battaglia,D.,et al.,Cognitive assessment in epilepsy surgery of children.Childs Nerv Syst,2006.22(8):p.744-59.
22.Carrascal,Y.,et al.,Cognitive decline after cardiac surgery:proposal for easy measurement with a new test.Interact Cardiovasc Thorac Surg,2005.4(3):p.216-21.
23.Steinmetz,J.and L.S.Rasmussen,[Cognitive deterioration after surgery]. Ugeskr Laeger,2008.170(49):p.4032-4.
24.Yoshitani,K.and Y.Ohnishi,[Cognitive dysfunction after cardiac surgery].Masui,2009.58(3):p.308-14.
25.Funder,K.S.,J.Steinmetz,and L.S.Rasmussen,Cognitive dysfunction after cardiovascular surgery.Minerva Anestesiol,2009.75(5):p.329-32.
26.Zhang,C.H.,et al.,[The effect of beating heart intracardiac procedures on postoperative cognitive function and SlOOb release:analysis of 51 patients].Zhonghua Yi Xue Za Zhi,2007.87(29):p.2054-7.
27.Soinne,L.,et al.,The effect of severe carotid occlusive disease and its surgical treatment on cognitive functions of the brain.Brain Cogn,2009.69(2):p.353-9.
28.Kalbe,E.,et al.,Frontal FDG-PET activity correlates with cognitive outcome after STN-DBS in Parkinson disease.Neurology,2009.72(1):p.42-9.
29.Gottesman,R.F.,et al.,Early postoperative cognitive dysfunction and blood pressure during coronary artery bypass graft operation.Arch Neurol,2007.64(8):p.1111-4.
30.Caza,N.,et al.,The effects of surgery and anesthesia on memory and cognition.Prog Brain Res,2008.169:p.409-22.
31.Smith,P.J.,et al.,Executive function and depression as independent risk factors for postoperative delirium.Anesthesiology,2009.110(4):p.781-7.
32.Diot,E.,et al.,[Favorable outcome of acute porphyric neuropathy after treatment with heme arginate].Rev Neurol(Paris),2007.163(11):p.1100-2.
33.Weber,C.F.,et al.,Impact of general versus local anesthesia on early postoperative cognitive dysfunction following carotid endarterectomy." GALA Study Subgroup Analysis.World J Surg,2009.33(7):p.1526-32.
34.Wei,J.L.,et al.,Improved behavior and sleep after adenotonsillectomy in children with sleep-disordered breathing.Arch Otolaryngol Head Neck Surg,2007.133(10):p.974-9.
35.Puskas,F.,et al.,Intraoperative hyperglycemia and cognitive decline after CABG.Ann Thorac Surg,2007.84(5):p.1467-73.
36.Xie,Z.,et al.,Isoflurane-induced apoptosis:a potential pathogenic link between delirium and dementia.J Gerontol A Biol Sci Med Sci,2006.61(12):p.1300-6.
37.Murkin,J.M.,Neurologic complications in noncardiac surgery.Semin Cardiothorac Vasc Anesth,2006.10(2):p.125-7.
38.Reichenberg,A.,et al.,Neuropsychiatric consequences of coronary artery bypass grafting and noncardiovascular surgery.Dialogues Clin Neurosci,2007.9(1):p.85-91.
39.Walker,M.D.,et al.,Neuropsychological features in primary hyperparathyroidism:a prospective study.J Clin Endocrinol Metab,2009.94(6):p.1951-8.
40.Paquot-Le Brun,C.,et al.,[Otologic sequels in velopalatine clefts.Analysis and management].Rev Stomatol Chir Maxillofac,2007.108(4):p.357-68.
41.Chiang,S.,et al.,Pharmacologic management of the older woman undergoing surgery.Womens Health(Lond Engl),2009.5(2):p.205-19.
42.Cook,D.J.,et al.,Postcardiac surgical cognitive impairment in the aged using diffusion-weighted magnetic resonance imaging.Ann Thorac Surg,2007.83(4):p.1389-95.