Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease

BACKGROUND: Hyperhomocysteinemia is a risk factor for vascular disease and potentially for dementia and depression. The most common cause of elevated homocysteine levels is deficiency of folate or vitamin B(12). However, patients with Parkinson disease (PD) may have elevated homocysteine levels resulting from methylation of levodopa and dopamine by catechol O-methyltransferase, an enzyme that uses S-adenosylmethionine as a methyl donor and yields S-adenosylhomocysteine. Since S-adenosylhomocysteine is rapidly converted to homocysteine, levodopa therapy may put patients at increased risk for vascular disease by raising homocysteine levels. OBJECTIVES: To determine whether elevations in plasma homocysteine levels caused by levodopa use are associated with increased prevalence of coronary artery disease (CAD), and to determine what role folate and vitamin B(12) have in levodopa-induced hyperhomocysteinemia. DESIGN/METHODS: Subjects included 235 patients with PD followed up in a movement disorders clinic. Of these, 201 had been treated with levodopa, and 34 had not. Blood samples were collected for the measurement of homocysteine, folate, cobalamin, and methylmalonic acid levels. A history of CAD (prior myocardial infarctions, coronary artery bypass grafting, or coronary angioplasty procedures) was prospectively elicited. We analyzed parametric data by means of 1-way analysis of variance or the t test, and categorical data by means of the Fisher exact test or chi(2) test. RESULTS: Mean +/- SD plasma homocysteine levels were significantly higher in patients treated with levodopa (16.1 +/- 6.2 micro mol/L), compared with levodopa-na?ve patients (12.2 +/- 4.2 micro mol/L; P<.001). We found no difference in the plasma concentration of folate, cobalamin, or methylmalonic acid between the 2 groups. Patients whose homocysteine levels were in the higher quartile (>or=17.7 micro mol/L) had increased prevalence of CAD (relative risk, 1.75; 95% confidence interval, 1.08-2.70;P=.04). CONCLUSIONS: Levodopa therapy, rather than PD, is a cause of hyperhomocysteinemia in patients with PD. Deficiency of folate or vitamin B(12) levels does not explain the elevated homocysteine levels in these patients. To our knowledge, this is the first report that levodopa-related hyperhomocysteinemia is associated with increased risk for CAD. These findings have implications for the treatment of PD in patients at risk for vascular disease, and potentially for those at risk for dementia and depression.     

Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients

Hyperhomocysteinemia is not only a major risk factor for atherothrombotic disease, but is also strongly associated with an increased risk of dementia and cognitive impairment, both of which are common in the course of Parkinson's disease (PD). Previous work has found that levodopa increases plasma homocysteine concentrations. Animal studies have indicated that the catechol-O-methyltransferase (COMT) inhibitors can prevent levodopa-induced elevation of homocysteine concentrations by reducing the O-methylation of levodopa. The objective of our study was to assess the impact of entacapone, a COMT inhibitor, on plasma levels of homocysteine, serum folate, and vitamin B12 in levodopa-treated PD patients. Nineteen PD patients receiving only levodopa and 21 PD patients on a combination of levodopa and entacapone participated in the cross-sectional study. The control group consisted of 17 subjects on dopamine agonists. The mean plasma homocysteine concentration in the subjects on only levodopa was higher than that in the subjects on a combination of levodopa and entacapone (P=0.001) or in the control group (P=0.0001). Concentrations of serum vitamin B12 and serum folate were on average normal in all groups, but levodopa-treated subjects (with or without entacapone therapy) were more prone to have hypovitaminosis B12 (45%) than controls on dopamine agonists (6%). We suggest that the COMT inhibition may play a promising role in successfully controlling levodopa-induced hyperhomocysteinemia and in reducing the risk of pathologies probably linked to it. These preliminary findings and postulated hypotheses must now be confirmed in prospective studies.     

Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations

BACKGROUND: An elevated plasma homocysteine (Hcy) level has been prospectively associated with an increased risk of vascular and degenerative dementias. An Hcy elevation is prevalent in patients with Parkinson disease (PD) in part because levodopa metabolism produces Hcy. The clinical relevance of an elevated Hcy level in patients with PD is unknown. OBJECTIVE: To determine if hyperhomocysteinemia in patients with PD is associated with depression or with cognitive or physical impairments. DESIGN: Ninety-seven people with a mean (SD) PD duration of 3.6 (1.6) years completed the Beck Depression Inventory, a battery of 11 cognitive tests, and the motor and function components of the Unified Parkinson's Disease Rating Scale. Normalized scores for the affective, cognitive, and physical measures were compared between those with a normal Hcy level (n = 66) and those with hyperhomocysteinemia (n = 31) (Hcy level, >1.89 mg/L [>14 micro mol/L]), controlling for age, sex, disease duration, and treatment. RESULTS: Subjects with an elevated Hcy level were slightly older (68 vs 62 years), but had similar plasma concentrations of vitamin B(12) and folate. Hyperhomocysteinemic patients were more depressed (P =.02) and had worse cognition (P<.01), but the physical measure did not differ. CONCLUSIONS: Patients with PD and hyperhomocysteinemia are more likely to be depressed and to perform worse on neuropsychometric tasks compared with normohomocysteinemic patients. Further research is warranted to see if hyperhomocysteinemia is a reversible risk factor for neuropsychiatric burden in patients with PD.     

创伤后应激障碍同型半胱氨酸水平

目的:探讨创伤后应激障碍(PTSD)患者早期的同型半胱氨酸水平.方法:汶川地震3个月后,对660例抗震志愿者进行PYSD问卷调查,对于可疑PTSD者给予结构性访谈,确诊53例PTSD.随机选取27例PTSD者(PTSD组),35例参加救灾的无PTSD人员(无PTSD组)及78例未参加抗震救灾的同单位人员(对照组),对其血浆同型半胱氨酸水平进行检测.结果:3组血浆同型半胱氨酸浓度均为非正态分布.运用等级资料检验发现,PTSD组与无PTSD组间以及无PTSD组与对照组间在同型半胱氨酸水平差异无显著性,而PISD组与对照组间存在显著的统计学差异. 结论:虽然目前仍不清楚同型半胱氨酸与PTSD间具体关系,但在PTSD的早期就存在血浆同型半胱氨酸水平的升高.     

Elevation of total homocysteine levels in patients with Parkinson's disease treated with duodenal levodopa/carbidopa gel

Levodopa/carbidopa (LD/CD) application elevates total plasma homocysteine (thcys). We determined thcys-, LD- and 3-O-methyldopa (3-OMD) concentrations in 28 patients with Parkinson??s disease (PD) on a LD/CD duodenal gel treatment. We found a distinct thcys increase (29.52?±?28.98???mol/l [median?±?SD]) above the 15???mol/l threshold and a significant (R?=?0.7) correlation between LD and 3-OMD. thcys ascent was observed in relation with the onset of atherosclerosis, non-motor symptoms and polyneuropathy in PD patients in the long term.     

Plasma homocysteine levels in pergolide-treated Parkinson disease patients

Hyperhomocysteinemia is as a risk factor for increased vascular disease in l-dopa-treated Parkinson disease (PD) patients. This effect of l-dopa is associated with the metabolism of l-dopa by methylation. This study aimed to assess the effect of pergolide on plasma homocysteine levels. Plasma homocysteine levels were compared between PD patients treated with pergolide as monotherapy, with l-dopa as monotherapy, or with an l-dopa and pergolide combination and compared with controls. Plasma homocysteine levels were significantly higher in the l-dopa monotherapy group, and there were no significant differences for the pergolide treatment groups. Pergolide can be beneficial for increased plasma homocysteine levels.     

Plasma homocysteine levels in multiple sclerosis

BACKGROUND: There is evidence that homocysteine contributes to various neurodegenerative disorders, and elevated plasma homocysteine levels have been observed in patients with multiple sclerosis (MS). OBJECTIVE: To investigate if and why plasma homocysteine levels are increased in MS, and whether they play a role in the disease course. METHODS: We compared plasma levels of homocysteine in 88 patients with MS and 57 healthy controls. In the MS group, 28 had a benign course, 37 were secondary progressive, and 23 primary progressive. To explore the underlying mechanisms, we measured serum levels of vitamins B6 and B12, folate, interleukin (IL)-12, tumour necrosis factor (TNF)-alpha, leukocyte nitric oxide production, and plasma diene conjugate levels (measure of oxidative stress). RESULTS: Mean (SD) plasma homocysteine concentration was higher in patients (13.8 (4.9) micromol/l) than in controls (10.1 (2.5) micromol/l; p<0.0001). However, there were no significant differences in homocysteine levels between the three clinical subgroups of MS. Serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and controls. In the MS group, there were no correlations between plasma homocysteine levels and the serum concentrations of IL-12 or TNF-alpha, leukocyte nitric oxide production, or plasma diene conjugate levels. CONCLUSIONS: Elevated plasma homocysteine occurs in both benign and progressive disease courses of MS, and seems unrelated to immune activation, oxidative stress, or a deficiency in vitamin B6, vitamin B12, or folate.     

The controversy concerning plasma homocysteine in Parkinson disease patients treated with levodopa alone or with entacapone: effects of vitamin status

Levodopa treatment of Parkinson disease results in hyperhomocysteinemia (HHcy) as a consequence of levodopa methylation by catechol-O-methyltransferase (COMT). Although inhibition of COMT should theoretically prevent or reduce levodopa-induced HHcy, results from several prospective studies are conflicting. Our review of these studies suggests that the ability of COMT inhibition to reduce or prevent levodopa-induced HHcy in Parkinson disease patients may be attributed to differences in the vitamin status of the study participants. In patients with low or low-normal folate levels, levodopa administration is associated with a greater increase in homocysteine and concomitant entacapone administration is associated with a greater reduction in homocysteine.     

丙戊酸单药治疗与癫痫患者血浆同型半胱氨酸水平间关系的Meta分析

目的分析癫痫患者血浆同型半胱氨酸水平变化与丙戊酸单药治疗间的关系。方法选择epileDsv、valproate、homocysteine和epilep。为检索词,计算机检索1990年1月-2013年8月美国国立医学图书馆、科学引文索引数据库、荷兰医学文摘等数据库,获得丙戊酸单药治疗与癫痫患者血浆同型半胱氨酸水平间关系的相关英文文献,均为丙戊酸单药治疗的癫痫患者与正常对照受试者血浆同型半胱氨酸水平比较的病例．对照临床研究。通过Newcastle—Ottawa量表独立进行文献质量评价和数据提取,Stata12．0统计软件行Meta分析。结果共纳入符合条件的英文文献8篇,包括266例行丙戊酸单药治疗的癫痼患者和489例正常对照受试者,所有纳入文献质量评分均〉6分。Meta分析显示,丙戊酸单药治疗组患者血浆同型半胱氨酸水平显著高于正常对照组[标准化均数差（SMD）：0．620,95％CI：0．320-0．920;P=0．000];经异质性检验存在显著异质性（I^2=65．600％,P=0．005）,根据不同地区和受试者年龄差异行进一步亚组分析,结果显示西亚组癫痫患者异质性风险（I^2=47．400％,P=0．107）较整体（I^2=65．600％,P=0．005）降低。采用敏感性分析评价Meta分析之稳定性,当任何一项研究被剔除后,相应的SMD值均不发生变化,表明分析结果稳定性良好。结论丙戊酸单药治疗可显著增加癫痫患者血浆同型半胱氨酸水平,后者是否受种族因素的影响尚待进一步研究。     

Relatively high levels of dopamine in nucleus accumbens of levodopa treated patients with Parkinson's disease

Summary The dopamine levels were found to be low in the putamen and relatively high in the nucleus accumbens in two Parkinson disease patients treated with levodopa up to the time of their deaths. Tyrosine hydroxylase immunocytochemistry revealed a severe degeneration of the nigro-striatal dopamine neuronal system in both postmortem brains. The relatively high dopamine levels in the nucleus accumbens may be responsible for the occurrence of dyskinesias.     

Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment

Cognitive and motor deficits have been proposed as markers of abnormal neurodevelopment in schizophrenia and have been associated with genetic liability. In a multicenter study involving 106 subjects, 56 with deficit schizophrenia and 50 with nondeficit schizophrenia, we tested the hypothesis that the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is associated with cognitive and motor deficits either in schizophrenia as a whole or in its deficit subtype. The COMT Val(158)Met polymorphism shared 6.6% of the executive/attention dysfunction variance in patients with schizophrenia and 15.6% of the motor impairment variance in patients with deficit schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only.     

血清同型半胱氨酸水平对首次抑郁发作患者认知功能的影响

目的研究血清同型半胱氨酸（Hcy）水平对首次抑郁发作患者认知功能的影响。方法选取 119例首次抑郁发作患者（病例组）及 117例健康志愿者（对照组）采用酶联免疫法测定两组患者的血清 Hcy水平,采用蒙特利尔认知评估量表（MoCA）进行认知功能评定。结果,与对照组相比,病例组患者血清 Hcy水平升高,MoCA量表的视空间 /执行功能、注意、抽象能力、延迟回忆、定向力和总分评分较低,异有统计学意义（P＜ 0.05）。病例组中高同型半胱氨酸血症（HHcy）组患者 MoCA量表的视空间 /执行功差能、注意、抽象能力、延迟回忆、定向力和总分评分较非 HHcy组低,差异有统计学意义（P＜ 0.05）。病例组血清 Hcy水平与 MoCA量表的视空间 /执行功能、注意、抽象能力、延迟回忆、定向力和总分评分呈负相关（r=-0.234~-0.215,P＜ 0.05）。结论首次抑郁发作患者存在认知功能障碍,血清Hcy代谢失衡与抑郁发作患者认知功能障碍相关。     

血浆同型半胱氨酸与迟发性运动障碍的关系

目的:探讨血浆同型半胱氨酸(Hey)与迟发性运动障碍(TD)的关系.方法:对33例伴TD的精神分裂症患者(TD组)与33例不伴,TD的精神分裂症患者(非TD组)进行血浆Hey与血清维生素B12、叶酸水平检测.结果:TD组血浆Hey水平显著高于非TD组,而血清叶酸水平显著低于非TD组.两组血浆Hey水平均与血清维生素B1...     

Ocular dyskinesias in patients with Parkinson's disease treated with levodopa

Abnormal involuntary eye movements were found in 8 of 27 patients with Parkinson's disease who were receiving levodopa and dopa decarboxylase inhibitors. The dyskinetic eye movements were smooth, slow, “to-and-fro” ocular deviations of large amplitude. They were suppressed by visual fixation and were prominent only in darkness or behind closed lids when patients were alert. They generally appeared in conjunction with involuntary body and limb movements but could occur alone. Many of the patients with ocular dyskinesias had prominent “on-off” responses to levodopa. Ocular dyskinesias were present in 8 of 10 patients with bodily dyskinesias. This suggests that if recording conditions are appropriate, these eye movements will commonly be found in patients with Parkinson's disease who develop abnormal involuntary bodily movements while they are receiving levodopa therapy.     

Longitudinal study of the levodopa motor response in Parkinson's disease: Relationship between cognitive decline and motor function

In this prospective study of 34 patients with Parkinson's disease (PD), measurements of the short duration levodopa motor response have been performed every 3 years in defined off states. The mean time from initiation of levodopa treatment was 14.8 years, and 17 patients survived to the latest assessment stage. Off phase motor function worsened at a yearly rate of 2.2% of the maximum disability score. The magnitude of the levodopa response is well preserved as the disease progresses, and patients who developed motor fluctuations maintained better on phase motor function than nonfluctuators (P = 0.01). Ten patients, of whom 5 survive, developed dementia. There was no difference in pretreatment disability or initial levodopa response between demented and nondemented subjects. However, dementia was associated with worse on and off motor disability scores after 11 and 14 years (P < 0.001), and a smaller levodopa response magnitude after 14 years (P = 0.008). The plot of sequential scores shows the association between cognitive decline and accelerating increase in motor disability. This suggests that the advanced phase of PD, when Lewy body pathology involves the cerebral cortex, progresses in an exponential rather than linear fashion. © 2009 Movement Disorder Society     

Mortality of patients with parkinson's disease treated with levodopa

Summary The effect of levodopa on the mortality of patients with Parkinson's disease was investigated in 349 patients treated with levodopa or levodopa combined with a decarboxylase inhibitor during 1969–1975 inclusive. During the study period, 61 patients died. The expected mortality was 32.99 resulting in a ratio of actual to expected deaths of 1.85. The excess mortality was accounted for by patients with a severe disease at entry and especially, by the less favorable effect of levodopa treatment than in the living patients. In comparison with the prelevodopa era, the reduction of mortality and the increase of life expectancy of patients with Parkinson's disease during levodopa treatment possibly reflect the decrease of the early mortality due to Parkinson's disease.

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Zusammenfassung Die Auswirkung der Levodopa-Behandlung auf die Mortalität von Parkinson-Patienten wurde anhand einer Serie von 349 Fällen untersucht, welche in den Jahren 1969–1975 einerseits mit L-Dopa, andererseits mit L-Dopa zusammen mit Decarboxylasehemmern behandelt wurden. Während der Beobachtungsperiode verstarben 61 Patienten. Die erwartete Mortalität hätte 32,99 betragen müssen, was eine Relation von tatsächlicher zu erwarteter Mortalität von 1,85 ergibt. Für die höhere Mortalität waren Fälle verantwortlich mit schweren Krankheitserscheinungen bei Beginn der Therapie und im besondern auch mit einem geringeren Effekt der L-Dopa-Therapie als bei den überlebenden Patienten. Verglichen mit den Beobachtungen vor Einführung der L-Dopa-Therapie beruht wohl die Verminderung der Mortalität und die erhöhte Lebenserwartung von Parkinson-Patienten unter L-Dopa auf der Abnahme der Frühtodesfälle durch die Parkinson'sche Krankheit.

     

The occurrence of motor fluctuations in parkinsonian patients treated long term with levodopa: role of early treatment and disease progression

The aim of this study is to evaluate what factors influence the risk of occurrence of motor fluctuations in patients with Parkinson's disease (PD) with particular reference to the role of early or delayed introduction of levodopa therapy during the course of the disease. One hundred twenty-five consecutive newly diagnosed patients with PD started levodopa treatment at the time diagnosis and were followed for 2 to 10 years. During follow-up, 60 patients had wearing-off or early morning akinesia. We estimated the cumulative time-dependent risk of motor fluctuation occurrence through a multivariable analysis. The risk was lower for patients with tremor-predominant PD, for those with shorter disease duration prior to levodopa, and for those who were relatively older at levodopa initiation. Our results suggest that, as far as motor fluctuations are concerned, disease prognosis is not influenced by early levodopa treatment. These observation support the introduction of levodopa as soon as there is a subjective need for the patients to maintain their level of social and work performance.