Hyperhomocysteinemia in ischemic stroke

In the past decade, elevated levels of plasma homocysteine have emerged as a potential risk factor for vascular disease. Homocysteine is central in the metabolism of multiple vitamins, including cobalamin and folic acid. There are many reasons for elevated homocysteine levels, but folate deficiency is the most common, even in developed countries. Prospective studies correlating risk of heart disease and homocysteine have provided conflicting data. Data are stronger for the risk of cerebrovascular disease being related to high homocysteine concentrations. Therapy for most patients involves vitamin replacement. Early trial data indicate that lowering of homocysteine may reduce vascular complications.     

No effect of folic acid supplementation in the course of 1 year on haemostasis markers and C-reactive protein in older adults

Elevated homocysteine levels are associated with an increased cardiovascular disease (CVD) risk, but the underlying mechanism is still unclear. High homocysteine might affect the endothelium, and consequently lead to impaired haemostasis. In a randomized placebo controlled trial among 276 older adults with plasma total homocysteine concentrations above 13 mM at screening, we investigated the effect of homocysteine lowering by folic acid supplementation (0.8 mg/day) for 1 year on markers of endothelial function (von Willebrand factor), coagulation (tissue factor, factor VIIa, fragments 1+2), and fibrinolysis (fibrin degradation products, tissue-type plasminogen activator), and inflammation (C-reactive protein). Despite a 24% reduction in plasma homocysteine concentration and four-fold increase in serum folate concentration in the folic acid group compared to the placebo group, there was no clear change in any of the haemostasis markers, nor CRP. Although homocysteine is associated with vascular disease risk in the general population, marked lowering of slightly elevated homocysteine concentrations by one-year folic acid supplementation does not influence haemostasis markers.     

Homocysteine and neurologic disease

Over the last 10 years, there has been an explosion of interest in homocysteine, a sulfur-containing amino acid that occupies a central location in the metabolic pathways of thiol compounds. This interest is primarily because of the realization that hyperhomocysteinemia is an important risk factor for vascular disease, including stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. Since elevated homocysteine levels can often be normalized by supplementing the diet with folic acid (folate), pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)), these observations raise the exciting possibility that this inexpensive and well-tolerated therapy may be effective in decreasing the incidence of vascular disease. In addition to its association with cerebrovascular disease, homocysteine may play a role in neurodegenerative disorders, even if only as a marker of functional vitamin B(12) deficiency. Homocysteine is also important to neurologists since most anticonvulsants raise homocysteine levels, an effect that may explain the teratogenic effects of these drugs. Practical knowledge concerning some details of homocysteine metabolism, the diagnosis of hyperhomocysteinemia, and the use of polyvitamin therapy to lower homocysteine levels will be increasingly important in the treatment of patients with neurologic disease. Arch Neurol. 2000;57:1422-1428     

Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, vitamin B12, folic acid and vitamin B6.

There is emerging evidence to support the unfavorable effects of some anti-epileptic drugs on the plasma homocysteine concentrations. Elevated homocysteine levels induced by anti-epileptic drug administration can theoretically increase not only the risk of vascular occlusive diseases, but also the risk of resistance to anti-epileptics and development of refractory epilepsy. To investigate the effect of common anti-epileptic drugs on the homocysteine metabolism, a total of 75 epileptic patients receiving phenytoin (n=16), carbamazepine (n=19), or valproic acid (n=22) and no anti-epileptic drug (n=18) were enrolled. Eleven age- and sex-matched healthy subjects served as the control group. Blood concentrations of homocysteine, folic acid, Vitamin B12 and pyridoxal 5'-phosphate (active circulating form of Vitamin B6) were measured. Compared to the control group, epileptic patients on anti-epileptic drug had higher blood levels of homocysteine. No difference in homocysteine concentrations was observed among epileptic patients in terms of the anti-epileptic drug used. Patients receiving phenytoin had significantly lower folic acid levels and those receiving carbamazepine had marginally lower pyridoxal 5'-phosphate levels in comparison with those using other anti-epileptic drugs. A negative correlation between homocysteine and folic acid concentrations was detected in epileptic patients on anti-epileptic drug. The duration of anti-epileptic drug use was correlated to the decrease of folic acid levels, but not with changes observed in homocysteine, Vitamin B12 and pyridoxal 5'-phosphate levels. No relationship between seizure frequency and homocysteine levels was observed in epileptic patients. Our results confirm that common anti-epileptic drugs has disadvantageous effects on homocysteine status. Because there was no significant change in homocysteine concentrations in epileptic patients who were not receiving an anti-epileptic drug, and no positive correlation between seizure frequency and homocysteine levels, we suggest that increase of homocysteine levels may be due to anti-epileptic drug use, rather than being epileptic in origin. Additionally, the underlying mechanism for homocysteine increase seems to be a decrease of cofactor molecules in patients using carbamazepine and phenytoin (pyridoxal 5'-phosphate and folic acid, respectively). However, changes observed are not related to the alteration in the levels of cofactors and remain unclear in the patients using valproic acid.     

Hyperhomocysteinemia in patients with dementia

Angiogenic brain damage and Alzheimer's disease caused by a progressing degenerative process are listed among the most frequent causes of dementia. These two processes are often concurrent and interrelated. Risk factors for vascular diseases including hypercholesteremia, arterial hypertension, and diabetes are also recognized risk factors for Alzheimer's disease. Results of many studies conducted in recent years suggest that the atheromatous process may be induced by elevated levels of homocysteine. Hyperhomocysteinemia first and foremost accelerates the onset of microangiopathic changes in small vessels. The mechanism underlying atherogenic action of homocysteine is still unclear. Hyperhomocysteinemia, generally assumed to have cytotoxic properties, damages endothelium in blood vessels, enhances thrombotic changes, and directly acts upon nitrogen oxide (NO), a vessel-dilating factor. Homocysteine is a metabolite of methionine. Homocysteine metabolism depends on current needs of the organism and involves either methionine reproduction (the reaction of remethylation, with such cofactors as B12 vitamin and folic acid), or cysteine synthesis (the transsulphuration reaction, with B6 vitamin as a cofactor). The normal range of plasma homocysteine concentration is assumed to be 5-14 mumol/L. The prevalence rates of hyperhomocysteinemia are 3-7% in the general population and 25% among those with vascular diseases. Elevated plasma homocysteine concentrations are due both to genetic and to environmental factors. In 2/3 of cases hyperhomocysteinemia is caused by decreased levels of folic acid, pyridoxine, and cobalamin. Deficiency of these vitamins is often seen in healthy elderly people.     

Homocysteine but not neopterin declines in demented patients on B vitamins

Summary. Inflammation and immune system activation seem to play an important role in the development and progression of dementia. Hyperhomocysteinemia is common in various forms of dementia, and a significant relationship was found between concentrations of homocysteine and immune activation marker neopterin. B vitamin supplementation is able to slow-down homocysteine formation in patients. In an open-label study, effects of B vitamin supplementation (Beneuran compositum ^?) on concentrations of homocysteine and neopterin were investigated in 58 patients with Alzheimer’s disease (n = 30), vascular dementia (n = 12) and mild cognitive impairment (n = 16). In all groups of patients, a significant percentage of patients presented with homocysteine concentrations >15 μmol/L and with elevated concentrations of immune activation marker neopterin. Decline of homocysteine concentrations was observed after one month of B vitamin supplementation (all p < 0.01; paired Kruskal-Wallisn-test). By contrast, neopterin concentrations remained unchanged (all p > 0.05). B vitamin supplementation in patients with various forms of dementia did not influence neopterin concentrations, which indicates that the degree of immune activation and inflammation remained unchanged. The question remains, if lowering of homocysteine by folate supplementation alone could have any beneficial effect to modulate the course of dementia development and if longer period of supplementation would also ameliorate immune system activation status.     

高同型半胱氨酸血症及其相关因素与青年脑梗死的关系

目的探讨同型半胱氨酸(homocysteine,Hcy)及其相关因素与青年脑梗死的关系。方法比较40例青年脑梗死患者(初发年龄<=45岁),30例神经系统非血管性疾病(NVD)患者和30例健康人血浆Hcy水平。分析年龄、性别、体重指数、肝肾功能、吸烟、嗜酒、血清VitBl2、叶酸水平的影响。结果脑梗死组血浆Hcy水平(21.4±18.8umol/L)分别与神经系统非血管疾病组(10.2±5.0umol/L)和健康对照组(12.9±8.6umol/L)比较差异均有显著性(P<0.01)。叶酸、VitB12与Hcy呈负相关,二者的降低与青年脑梗死关系密切(P<0.01)。血肌苷增高和吸烟与Hcy增高有关(P<0.05)。男性Hcy显著高于女性(P<0.05)。结论Hcy和青年脑梗死密切相关,与叶酸、VitBl2呈负相关,与肌苷呈正相关。男性、吸烟也与Hcy增高有关。     

Homocysteine,apolipoproteine E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment

BACKGROUND: Alzheimer's disease (AD) is the most common dementia disorder in elderly people. Currently, the only known genetic factor associated with the development of sporadic AD is the apolipoprotein E (ApoE) 4 allele. There is a need to identify other environmental and genetic risk factors that could modulate the risk of developing sporadic AD. OBJECTIVE: To analyse the correlation between the ApoE and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma homocysteine levels and vitamins (B(12) and folic acid) concentrations in serum from patients with AD and mild cognitive impairment (MCI) as compared with control group. METHODS: The study was carried out in 99 AD patients, 98 subjects with MCI and 100 healthy subjects. Diagnosis of probable AD was made according to the NINCDS-ADRDA and DSM-IV criteria. The following factors were analysed: age, gender, duration of disease, concentration of plasma total homocysteine, folic acid and vitamin B(12) in the serum and the polymorphism of MTHRF and ApoE genes. The results obtained were analysed by multivariate analysis of regression. RESULTS: We found that plasma total homocysteine is increased in AD patients (p < 0.0001) and depended on the MTHFR T/T genotype in the presence of low folate levels (p < 0.05). The increased frequency of ApoE4 allele in the AD population was independent of homocysteine, folic acid and vitamin B(12) levels and MTHFR status. CONCLUSIONS: We conclude that the concentration of plasma total homocysteine is increased in AD patients. This may be associated with the T/T genotype in the MTHFR gene; however, the distribution of the MTHRF C677T polymorphism in the Polish population does not differ in AD and controls.     

Folic acid supplementation in dementia: a preliminary report

Recent work on high plasma homocysteine levels in patients at risk for developing Alzheimer's disease has led to the hypothesis that folic acid supplementation might reduce risk in such patients. The authors report on the effects of folic acid 10 mg/day versus placebo on 11 patients (only 7 completers) with dementia and low-normal folic acid levels. This is the first study evaluating folic acid or placebo in patients with dementia. Subjects had low-normal baseline folic acid levels. The magnitude of change between baseline and second testing was not statistically significant between the 2 groups. However, there was a trend for the folate group to perform worse on two specific cognitive measures, suggesting a possible trend toward worsening of some cognitive abilities after the folic acid. The folic acid in very high doses was well tolerated. Larger studies are necessary before empirically administering folic acid to patients already suffering from dementia.     

AD患者血清Hcy叶酸及维生素B_(12)与认知功能减退的关系研究

目的研究维生素B_(12)和叶酸水平以及同型半胱氨酸是否对阿尔茨海默症(AD)患者存在潜在影响。方法运用美国国立神经病学、语言障碍和卒中-阿尔茨海默病和相关疾病学会(NINCDS-ADRDA)标准严格筛选AD患者95例。从体检中心选取年龄、性别及受教育程度匹配的无脑血管病、无认知障碍的健康对照组76例。采用化学发光微粒子免疫分析法检测171例年龄≥50岁的老年痴呆患者血清维生素B_(12)和叶酸水平。采用肝素抗凝的血浆进行循环酶法Hcy测定。探讨血清低水平维生素B_(12)和叶酸以及高水平同型半胱氨酸是否是老年痴呆发生的危险因素。认知功能的评价采用目前通用的神经心理测试:中文版简易精神状态检查表(MMSE)。采用Logistic回归分析评估血清维生素B_(12)、叶酸以及同型半胱氨酸与老年痴呆患病风险的关系。结果 171例中153例叶酸正常,其中对照组79例(51.63%),实验组74例(43.27%);124例维生素B_(12)正常,其中对照组60例(48.39%),实验组64例(51.61%);101例同型半胱氨酸正常,其中对照组51例(50.50%),实验组50例(49.50%)。作各协变量调整后,AD患者血清维生素B_(12)及叶酸水平以及同型半胱氨酸与CMMES评分无相关性(P0.05)。但低血清维生素B_(12)水平以及低叶酸水平与AD患病风险相关。结论血清维生素B_(12)和叶酸水平以及同型半胱氨酸水平与AD患者认知功能之间无明显关联。低水平维生素B_(12)以及低水平叶酸可能通过某种机制增加AD患病风险,低水平同型半胱氨酸可能通过某种机制降低AD患病风险。