Relationship Of Plasma Homocysteine Level And Polymorphysims Of MTHFR Gene With Post-stroke Depression

IntroductionPost-stroke depression is a common complication after stroke.Folstein first reported that post-stroke depression is a common accompanying symptoms after stroke.A multi-center study showed that about 61% of stroke patients suffer depression. At present, there is a not clear definition for PSD.The definition of PSD is generally agreed that there are different degrees of post-stroke depressive symptoms and the symptoms persisted for more than 2 weeks.PSD of the overall incidence rate is 40%-50%,and the incidence rate of acute perior is about 33%, while the incidence rate of recovery was slightly higher.The incidence depression of female is two times than men.PSD patients have decreasing of interest to participate in activities and extend recovery time,resulting in reducing medication compliance,increasing the physical and mental burden, affecting daily life, study and work, increasing family and social burden.Stroke is a kind of disease for acute cerebrovascular disease.According to the Fourth National cerebrovascular Conference,stroke is divided into hemorrhagic stroke and ischemic stroke.Hemorrhagic stroke include cerebral hemorrhage and subarachnoid hemorrhage.Ischemic stroke include cerebral thrombosis, cerebral embolism, lacunar infarction and transient ischemic attack. With the development of treatment technique, the harm by stroke itself had declined, but depression which one of the complications caused by stroke have cause more and more attention.According to DSM-IV diagnosis of depression, patient have the depressed mood which is not commensurate to the situation. Causes of depression can be summarized as biological factors and social psychological factors.Biological factors is the main factor. Biological factors include three aspects:The first aspect for genetic predisposition, people who have family history of depression suffering depression is two times than the general population;the second aspect for neural transmitter changes,and there are two theories:(1) Monoamine hypothesis:This hypothesis was put forward in 1960s, that depression is caused by brain monoamine neurotransmitters (noradrenaline (NE) and 5-Hydroxytryptamine (5-HT))insufficiency;(2) Receptor hypothesis:In 1970s researchers proposed that depression is the increasing sensitivity of NE/5-HT receptor;(3)Neuroendocrine studies:the depressed patients have hypothalamus-pituitary-adrenal axis dysfunction and high level of plasma cortisol, urinary cortisol and its metabolites.The pathogenesis of PSD is not yet clear. In recent years, scholars have conducted a series of studies on PSD, generally regarding PSD is caused by social psychology, neural anatomy,neurobiology and other factors mediating.Recently,the pathogenes of PSD is summarized as following three aspects:(1) post-stroke depression and stroke lesions related research:Robinson regards that stroke lesions determine the incidence of post-stroke depression. The left front and left hemisphere lesions involving the subcortical and dorsal lateral of the left frontal lobe were more likely to have PSD.The lesions were closer to the frontal lobe with PSD has higher incidence. NE and 5-HT neurons locate in brainstem.The axons go through the hypothalamus and the basal ganglia area, forming frontal/temporal lobe-basal ganglia-brain stem ventral loop.The loop is responsible for regulating mood, sleep and cognition.When the lesions involving the above loop, the imbalance of NE and 5-HT and the loop are damaged,leading to depression. Frishkoff found that PSD patients with left hemisphere frontal N400 effect appeared earlier and held longer than other parts. But some scholars believed that post-stroke depression has nothing to do with the stroke lesions. Therefore, the correlation of post-stroke depression and stroke lesion has not yet any consensus. (2) The correlation of post-stroke depression and neurotransmitters:NE and 5-HT is an important neurotransmitter of the nervous system, closely relating to human emotion and spiritual activities. A decline of NE and 5-HT may cause depression. Stroke may damage NE and or 5-HT neurons, and it will decrease NE and 5-HT synthesis., or it will decrease the 5-HT receptor number and sensitivity of postsynaptic membrane,leading to depression. (3) Post-stroke depression and nerve nutrition-related research:brain-derived neurotrophic factor is a neurotrophic key member of the family, and it is involved in nerve regeneration, differentiation and injury repair.In recent years,many scholars have studied that homocysteine is not only relevant with stroke, but also has positive correlation with depression. Bottiglieri found that serum total Hcy levels of 50% depressed patients was higher than the control group. Tolmunen found that the degree risk of depression increased with the higer blood levels of total Hcy.Homocysteine (Hcy) is a key intermediate metabolite in methionine metabolism.There are two ways:the most important way is through the N5-methyl tetrahydrofolate offer methyl to Hcy and change to methionine. This approach requires folate and vitamin B12. N5-methylenetetrahydrofolate is generated by the N5,N10-methylenetetrahydrofolate reductase (MTHFR) catalyzing N5,N10-methylen-etetrahydrofolate.The other way is through cystathionine synthase (CBS) reduction catalyzing synthesis of cystathionine,which further generates cysteine and keto acid. Hcy inducing depression may be related to the following three aspects:(1) The increasing of Hcy affects monoamine neurotransmitters methylation. (2) Hcy leads to inhibition of sodium and potassium ATP enzyme and may be related to depression. (3) Hcy and its metabolites can serve as agonists of ion channels and several metabotropic glutamate receptor,leading to neurotoxicity. NE and 5-HT is an important neurotransmitter causing depression. Elevating level of plasma Hcy leads to reduce the formation of s-adenosylmethionine(SAM),and then it will make NE can not be methylated to adrenaline, causing accumulation of NE in the nerve endings. When the nerve endings of the NE concentration is too high, it will feedback and inhibit biosynthesis of NE vesicles. When the impulse reaches the nerve endings, NE released into the synaptic will decrease, which led to the emergence of depression. Some studies have found that the role of Hcy in the mechanisms of neurotransmitters is by inhibiting catecholamine and enzymes which catalyze SAM methylation reactions.Reynols firstly suggested homocysteine-methyl donor pathway and the relationship with depression in 1970s. Bryen have already proved that Hcy is related to neurotransmitters. The most direct proof of the research found that depressed patients with high blood Hcy levels have decreasing cerebrospinal fluid of SAM,5-HT and NE.Indirect studies showed SAM could be used as antidepressants,which are superior to placebo and tricyclic antidepressants.Hcy methylation in the course of some rate-limiting enzyme, such as MTHFR, CBS and MS,and MTHFR is the key enzyme. MTHFR gene is located on human chromosome lp36.3.It includes 11 exons and 10 introns and 212 kb cDNA. MTHFR gene has at least seven location with C→T base variation, which are located in 559,677,692,764,985,1015 and 1 081.The present study suggests that in exon 4,the C677T mutation is the most common one. C677T (Ala→Val) mutation can produce Hinfl enzyme restriction sites, so it changes MTHFR enzyme heat sensitivity and activity.In homozygous mutation,enzyme is only 30% of normal activity.In heterozygous mutation,enzyme is 65% of normal activity. Many studies have proved that MTHFR gene 677C→T mutation caused decreasing enzyme activity, which increased the blood levels of Hcy. Osvaldo found that blood Hcy of TT genotype participants was 0.19mg/L higer than CC genotype. Elderly population study in Norway found that TT genotype was related to depression, but not TT genotype has nothing to do with depression. In other studies also found that the 677C→T mutation had a positive correlation with depression.Objective:This study aimed at researching the relationship of high Hcy and MTHFR gene polymorphism with post-stroke depression.Methods:The blood samples were from the neurology Department of Zhu Jiang Hospital and it is diagnosized of the Fourth National cerebrovascular Conference and Hamilton depression scale.Patients were divided into two groups:50 cases of stroke patients (32 cases of men and 18 cases of female) and 59 cases of post-stroke depression patients(38 cases of men and 21 cases of female). Plasma Hcy concentration is examed by Fluorescence polarization immunoassay.Blood is pumped about 2mL, and then it is anticoagulated and extracted peripheral blood leukocyte genomic DNA by phenol-chloroform extraction method.Polymerase chain reaction-restriction fragment length polymorphism technology was applied and 5'-T GA A GG A GA A GGT GT CT G CGG GA-3'in upstream and 5'-A GG A CGGT G CGG T GA GA GT G-3 in downstream were used for amplification of MTHFR gene.Hinf I enzyme was used for detecting 677C→T polymorphism of MTHFR gene. SPSS13.0 statistical package was employed in the comparison of genotype frequency. Chi-squaretest was used to calculate the blood Hey level,allele frequency and mutation frequency in stroke and post-stroke depression patients.Results:1.To compare the plasma Hey levelsThe plasma levels of Hey in the PSD group were significantly higher than those in the stroke group.There was a higher incidence of hyperhomoeysteine in PSD group than ine stroke group.No difference of Hey levels was investigated between male and female in both PSD group and stroke group.Hey levels of any genotypes in PSD group are higher than that of corresponding genotypes in stroke group.Plasma Hey levels of TT genotype in PSD group was obviously higher than those of CT and CC genotype.2.The Polymorphisms of MTHFR gene C677TThe distributions of MTHFR gene C677T polymorphism in PSD group and stroke group were all in accordance with the law of Hardy-Weinberg equilibriums (P>0.05).Tlhere were significant differences in genotype frequencies and allele frequencies between PSD group and stroke group.Tallele frequency in PSD group is higher than that in stroke group.For PSD, the odds ratio for T tallel gene versus C tallel gene was 2.510,95%CI was 1.452-4.338,Conclussion:1. Plasma Hey and considence of high Hey in PSD group is higher than the stroke group.Elevation in plasma Hey levels should be a risk factor of PSD.Plasma Hey levels may be used to Predict the severity of PSD. 2. With TT genotype and T tallele gene have important effect on plama Hcy.This study has found that sex and age have little effect on plama Hcy.3. The Polymorphisms of MTHFR C677T may be hereditary Predisposing factor of PSD, which may be included in the onset and clinical situation of PSD by influencing levels of Hcy.