亚甲基四氢叶酸基因多态性与阿尔茨海默病精神行为症状的相关性分析

Correlation between MTHFR gene polymorphism and mental and behavioral symptoms of Alzheimer’s disease

目的探索亚甲基四氢叶酸(MHTFR)的基因多态性、同型半胱氨酸(Hcy)水平与阿尔茨海默病(AD)及痴呆的行为心理症状(BPSD)发生的相关性。方法收集南方医科大学顺德医院神经内科于2018年7月1日-2020年3月28日诊治的148例AD患者的临床资料。其中,90例符合纳排标准的AD患者被纳入病例组。根据是否伴有BPSD进一步分为AD-BPSD(有BPSD的AD患者,33例)和AD-NON BPSD(无BPSD的AD患者,57例)亚组。收集门诊和(或)病房同期诊治的58例初诊为非致残型脑卒中患者,纳入对照组。收集入组患者的年龄、性别、AD家族史、受教育程度(初级为文盲或小学或初中毕业,高级为高中毕业或取得学士学位)、吸烟史、高血压病史、糖尿病病史、血维生素B_(12)水平、血Hcy水平、MTHFR基因多态性等资料。对病例组患者行简易智力状态检查量表(MMSE量表)、蒙特利尔认知评估量表(MoCA量表)中文版、神经精神科问卷(NPI)等检测。应用DNA微阵列技术检测患者MTHFR基因多态性。结果3组患者年龄、性别的差异均无统计学意义(P值均>0.05)。AD-BPSD组MMSE量表和MoCA量表评分、血维生素B_(12)水平均显著低于AD-NON BPSD组和对照组,血Hcy水平及携带TT型MTHFR677等位基因的患者比例显著高于AD-NON BPSD组和对照组,病程时长显著长于AD-NON BPSD组(P值均<0.05)。与对照组相比,AD-NON BPSD组及AD-BPSD组高级教育程度、有吸烟史及AD家族史的患者比例显著升高(P值均<0.05)。多元logistics回归分析显示,MTHFR基因型(OR为1.10,95%CI为1.04~1.45,P=0.034)、血Hcy水平(OR为1.21,95%CI为1.09~1.48,P=0.021)、血维生素B_(12)水平(OR为0.89,95%CI为0.71~0.99,P=0.026)、有AD家族史(OR为1.18,95%CI为1.07~1.26,P=0.046)及患者受教育程度(OR为0.78,95%CI为0.65~0.93,P=0.032)为AD发生的影响因素(P值均<0.05);TT型MTHFR基因(OR为1.24,95%CI为1.07~1.85,P=0.033)、血维生素B_(12)水平(OR为0.69,95%CI为0.38~0.96,P=0.041)、血Hcy水平(OR为1.34,95%CI为1.12~3.16,P=0.023)及有AD家族史(OR为0.88,95%CI为0.72~0.98,P=0.032)则是AD患者发生BPSD的影响因素(P值均<0.05)。结论MTHFR 677 TT等位基因频率、血Hcy及维生素B_(12)水平是AD患者发生BPSD的影响因素,是可能的干预靶点。

Objective To explore the role of MTHFR gene polymorphism and homocysteine(Hcy)level in Alzheimer’s disease(AD)and behavioral and psychological symptoms of dementia(BPSD).Methods Clinical data of 148 AD patients admitted to our hospital between July 1,2018 and March 28,2020 were collected.Among them,90 patients who met the inclusive and exclusive criteria were divided into AD-BPSD group(n=33)and AD-NON BPSD group(n=57).Meanwhile,58 patients with primary non-disabling stroke treated in the outpatient and/or ward were enrolled in control group.Age,sex,family history,education background(junior:illiteracy,primary school or junior high school level;senior:senior high school or undergraduate level),smoking history,hypertension history,diabetes history,serum vitamin B_(12) level,Hcy,and MTHFR gene polymorphisms were investigated.AD patients were evaluated by mini-mental state examination(MMSE),Montreal Cognitive Assessment(MoCA)and neuropsychiatric inventory(NPI)questionnaire.DNA microarray was used to detect MTHFR gene polymorphism.Results There were no significant differences in the age or gender composition among the three groups(all P>0.05).The scores of MoCA and MMSE and vitamin B_(12) level in AD-BPSD group were significantly lower than those in AD-NON BPSD group and control group,while Hcy level and proportion of patients with MTHFR 677 TT genotype in AD-BPSD group were significantly higher than those in AD-NON BPSD group and control group(all P<0.05).The course of disease of AD-BPSD group was significantly longer than that of AD-NON BPSD group(P<0.05).Compared with the control group,the proportion of patients with senior education level,smoking and positive family history in AD-NON BPSD group and AD-BPSD group increased significantly(all P<0.05).Multifactor logistic regression analysis showed that MTHFR genotype(OR=1.10,95%CI:1.04-1.45,P=0.034),Hcy level(OR=1.21,95%CI:1.09-1.48,P=0.021),vitamin B_(12) level(OR=0.89,95%CI:0.71-0.99,P=0.026),AD family history(OR=1.18,95%CI:1.07-1.26,P=0.046)and education level of patients(OR=0.78,95%CI:0.65-0.93,P=0.032)were correlated with the occurrence of AD(all P<0.05).MTHFR 677 TT genotype(OR=1.24,95%CI:1.07-1.85,P=0.033),vitamin B_(12) level(OR=0.69,95%CI:0.38-0.96,P=0.041),Hcy level(OR=1.34,95%CI:1.12-3.16,P=0.023),and AD family history(OR=0.88,95%CI:0.72-0.98,P=0.032)were influencing factors for BPSD(all P<0.05).Conclusion The MTHFR 677 TT allele frequency,and Hcy and vitamin B_(12) levels are independent relevant factors for BPSD and are potential intervention targets.