左旋多巴治疗帕金森病所致高同型半胱氨酸血症的研究

Effect of L-dopa treatment on hyperhomocysteinemia in patients with Parkinson’s disease

目的 探讨血浆同型半胱氨酸（Hcy）水平与左旋多巴（L-dopa）治疗帕金森病（PD）的相关性。方法 依据英国脑库PD诊断标准，从2011年5月至2013年3月来北京大学第五临床医学院神经内科住院及门诊就诊的患者中入选，一共收集PD组161例，其中男性88例，女性73例，年龄（64.36±11.06）岁，病程范围：0.5～22（6.3±5.4）年。比较PD组和正常对照组Hcy，维生素B12、叶酸水平与L-dopa治疗时间、剂量，运动并发症、焦虑、抑郁和痴呆发生率的相关性，并对PD伴高同型半胱氨酸血症（HHcy）的原因进行分析，同时还对PD组（161例）和正常对照组（240例）MTHFR基因和COMT基因多态性进行分析。结果 161例PD患者平均血浆Hcy水平（17.65±9.36）μmol/L，明显高于正常对照组（10.12±3.20）μmol/L（P＜0.001）。纳入分析的6个因素（包括性别、年龄、L-dopa治疗时间、剂量、叶酸和维生素B12浓度）单因素分析发现，L-dopa治疗对影响HHcy有统计学意义（P＜0.01）。导致PD患者HHcy的原因分析结果以正常叶酸和维生素B12水平为主，＞84%，间接提示HHcy可能与Hcy代谢途径中的相关酶的基因突变有关。本研究PD组与正常对照组COMT和MTHFR基因多态性的分布无统计学差异（P＞0.05），但对PD组按Hcy水平进行分层分析结果显示，C677T基因型及等位基因在HHcy患者（＞15μmol/L）和Hcy正常患者（＜15μmol/L）的频率分布差异有统计学意义（P＜0.05）。另外，161例PD患者中有77例伴有HHcy，剔除未治疗组22例外，余55例中有运动波动症者35例（63.6%），有异动症者3例（5.5%），有焦虑和抑郁30例（54.5%），有痴呆者12例（21.8%）。结论 L-dopa治疗的PD患者容易产生HHcy，HHcy可以使L-dopa治疗后运动并发症、焦虑、抑郁和痴呆的发生率增加或病情加重。

Objective To determine the relationship of the plasma homocysteine （Hcy） level with Parkinson’s disease （PD） with or without L-dopa treatment. Methods According to the UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria, 161 identified PD in- and out-patients admitted in the Fifth Hospital of Peking University from May 2011 to March 2013 were enrolled in this study. They were 88 males and 73 females, at age of （64.36±11.06） years, and suffered from PD for 0.5？22 （6.3±5.4） years. Another 80 age- and sex-matched healthy volunteers taking physical examination during the same period served as normal controls. The plasma levels of Hcy, Vit B12 and folic acid were measured and compared between the 2 groups. Univariate linear regression analysis was carried out for the correlation of the plasma levels of Hcy, Vit B12 and folic acid with the duration and dosage of L-dopa treatment, motor complications, anxiety, depression and dementia incidence. The causing factors of hyperhomocysteinemia （HHcy） in PD patients was also analyzed. The polymorphisms of MTHFR and COMT genes were detected in the 161 PD patients and 240 normal individuals. Results The plasma Hcy level was （17.65±9.36）μmol/L for the 161 PD patients, which was significantly higher than that in the normal controls [（10.12±3.20）μmol/L, P〈0.001]. Among the 6 factors （sex, age, duration and dosage of L-dopa treatment, plasma levels of folic acid and Vit B12）, univariate linear regression analysis showed that L-dopa treatment caused the incidence of HHcy （P〈0.01）. The causes of HHcy were mainly normal folate and Vit B12 levels in PD patients （more than 84%）, which indirectly suggesting that there were some mutations in the relative enzymes regulating the metabolism of Hcy. There was no obvious difference in the distribution of COMT and MTHFR polymorphism between PD group and control group （P〉0.05）. Based on Hcy level, PD patients were subdivided into HHcy and mormal Hcy group, the frequency distributions of C677T alleles and genotypes were significantly different between HHcy group and normal Hcy group. There were 77 PD patients out of 161 with HHcy. Excluding 22 cases without L-dopa treatment, there were 35 from the left 55 cases having motor fluctuations （63.6%）, 3 having dyskenisia （5.5%）, 30 having anxiety and depression （54.5%）, and 12 having dementia （21.8%）. Conclusion PD patients with L-dopa treatment are prone to having HHcy, and HHcy exacerbates the severities or increases the incidences of motor complications, anxiety, depression and dementia in PD patients with L-dopa treatment.