tHcy Levels Research Articles

Homocysteine, antioxidant vitamins and lipids as biomarkers of neurodegeneration in Alzheimer's disease versus non-Alzheimer's dementia.

Evidence for the benefit of antioxidants' based therapeutic intervention in dementia are inconsistent. Parallel studies in disease forms of dementia different than Alzheimer's are even less conclusive. In this study, the role of serum levels of homocysteine (tHcy), lipids and antioxidants in predicting the risk of cognitive decline in Alzheimer's disease (AD) versus non-Alzheimer's dementias (n-AD). The objective was to add to the ongoing cumulative research to establish the biochemical baseline for potential nutri-therapeutic intervention in different forms of dementia. 65 participants with dementia (DP-s) were divided into two groups: ADP--patients with Alzheimer's disease and n-ADP--patients with dementia of a different etiology than primary neurodegenerative dementia in the course of Alzheimer's disease. Cognitive function was assessed by Mini-Mental State Examination (MMSE) and related to plasma levels of tHcy, folate, vitamins B-6, B-12, lipids and vitamins A and E for both groups. Also examined were associations between cognitive impairment and several variables (age, education, duration of dementia) that might confound nutrition-cognition associations. A significant reduction in serum vitamin A levels and elevation of total cholesterol levels were shown for the DP-s group compared to those in the control group. Moreover, significant differences were found in MMSE data and serum vitamin E and tHcy levels between patients with ADP and n-ADP. The scores for MMSE showed a correlation with the vitamin E levels and duration of dementia in the ADP group and/or correlation with tHcy, levels of vitamins A and/or E, and duration of dementia in the n-ADP group. The results obtained suggest that elevated serum tHcy and decreased levels of vitamins A and E are associated with an increased risk of non-Alzheimer's dementias, although further studies involving a larger cohort are now needed to verify these results.

Motor development related to duration of exclusive breastfeeding, B vitamin status and B12 supplementation in infants with a birth weight between 2000-3000g, results from a randomized intervention trial.

BackgroundExclusive breastfeeding for 6 months is assumed to ensure adequate micronutrients for term infants. Our objective was to investigate the effects of prolonged breastfeeding on B vitamin status and neurodevelopment in 80 infants with subnormal birth weights (2000-3000 g) and examine if cobalamin supplementation may benefit motor function in infants who developed biochemical signs of impaired cobalamin function (total homocysteine (tHcy) > 6.5 μmol/L) at 6 months.MethodsLevels of cobalamin, folate, riboflavin and pyridoxal 5´-phosphate, and the metabolic markers tHcy and methylmalonic acid (MMA), were determined at 6 weeks, 4 and 6 months (n = 80/68/66). Neurodevelopment was assessed with the Alberta Infants Motor Scale (AIMS) and the parental questionnaire Ages and Stages (ASQ) at 6 months.At 6 months, 32 of 36 infants with tHcy > 6.5 μmol/L were enrolled in a double blind randomized controlled trial to receive 400 μg hydroxycobalamin intramuscularly (n = 16) or sham injection (n = 16). Biochemical status and neurodevelopment were evaluated after one month.ResultsExcept for folate, infants who were exclusively breastfed for >1 month had lower B vitamin levels at all assessments and higher tHcy and MMA levels at 4 and 6 months. At 6 months, these infants had lower AIMS scores (p = 0.03) and ASQ gross motor scores (p = 0.01).Compared to the placebo group, cobalamin treatment resulted in a decrease in plasma tHcy (p < 0.001) and MMA (p = 0.001) levels and a larger increase in AIMS (p = 0.02) and ASQ gross motor scores (p = 0.03).ConclusionsThe findings suggest that prolonged exclusive breastfeeding may not provide sufficient B vitamins for small infants, and that this may have a negative effect on early gross motor development. In infants with mild cobalamin deficiency at 6 months, cobalamin treatment significantly improvement cobalamin status and motor function, suggesting that the observed impairment in motor function associated with long-term exclusive breastfeeding, may be due to cobalamin deficiency.Clinical trial registrationClinicalTrials.gov, number NCT01201005

Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors

Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia. The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors. Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 μmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia. In the 643 subjects (age: 67.2 ± 8.4 years, male: 59% ; education: 12.9 ± 2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2-13), 47 patients were diagnosed with dementia (Alzheimer's disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE ɛ4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p = 0.043) and the highest tertile of tHcy (HR: 2.50, p = 0.047) for all-cause dementia remained significant. Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk.

Clinical presentation, gene analysis and outcomes in young patients with early-treated combined methylmalonic acidemia and homocysteinemia (cblC type) in Shandong province, China

ObjectivesTo estimate the incidence of MMA on newborn screening in Shandong province from May 2011 to May 2014 and summarize the clinical presentation, biochemical features, mutation analysis, and treatment regime of early-treated patients with cblC disease. MethodsBetween May 2011 and May 2014, 35,291 newborns were screened for MMA in Jinan maternal and Child Care Hospital, Shandong province. The levels of C3, C3/C2, methionine and tHcy were measured. Most patients received treatment with intramuscular hydroxocobalamin after diagnosis. Metabolic parameters, clinical presentation and mental development were followed up. ResultsNine patients were identified among 35,291 by newborn screening, giving an estimated incidence of 1:3920 live births for MMA, and all were classified as cblC disease. Among them, five patients received treatment with intramuscular hydroxocobalamin and two patients did not receive any treatment. One patient died of metabolic crises triggered by infection at the age of 38days. Seven different mutations (c.609G>A, c.455_457delCCC, c.394C>T, c.445_446insA, c.658_660delAAG, c.452A>G and IVS1+1G>A) were detected. The mutations (c.455_457delCCC and IVS1+1G>A) are novel. Five patients who received treatment had favorable metabolic response, with both reduction of urine MMA and tHcy and increase of methionine. We obtained 7 records of DQ assessment. The five patients who received treatment presented with developmental delay and obvious neurological manifestations. In two patients who did not receive any treatment, case 8 presented with severe mental retardation and developmental delay, while case 9 had nearly normal DQ values at the age of 11/12years. ConclusionOur study characterized variable phenotypes of neurodevelopment in early-treated cblC patients diagnosed on newborn screening. The long-term outcomes of cblC disease are unsatisfactory in spite of conventional treatment and improvement of biochemical abnormalities. Although the number of patients is too small, the information provided in this work is of value in highlighting possible genotype–phenotype correlation that influences outcomes in cblC disease by future studies.

Vitamin B2, vitamin B12 and total homocysteine status in children and their associations with dietary intake of B-vitamins from different food groups: the Healthy Growth Study

To examine the associations between the dietary intakes of certain B-vitamins from different food sources with the relevant plasma status indices in children. A representative subsample of 600 children aged 9-13years from the Healthy Growth Study was selected. Dietary intakes of vitamins B2, B12, B6 and folate derived from different food sources were estimated. Plasma levels of vitamin B2 (or riboflavin), methylmalonic acid (MMA) and total homocysteine (tHcy) were also measured. Plasma concentrations of vitamin B2 below 3μg/L were found in 22.8% of the children. Children in the lower quartile of dietary vitamin B2 intake were found to have the lowest plasma vitamin B2 levels compared to children in the upper three quartiles (5.06±7.63 vs. 6.48±7.88, 6.34±7.63 and 6.05±4.94μg/L respectively; P=0.003). Regarding vitamin B12 children in the lower quartile of dietary intake had higher mean plasma tHcy levels compared to children in the upper two quartiles, respectively (6.00±1.79 vs. 5.41±1.43 and 5.46±1.64μmol/L; P=0.012). Positive linear associations were observed between plasma vitamin B2 levels and dietary vitamin B2 derived from milk and fruits (β=0.133; P=0.001 and β=0.086; P=0.037). Additionally, nonlinear associations were also observed between plasma vitamin B2 levels and vitamin B2 derived from red meat, as well as between tHcy levels and vitamins B12 and B6 derived from milk; vitamins B12, B6 and folate derived from cereal products and folate derived from fruits. A considerably high prevalence of poor plasma vitamin B2 status was observed in children. The intake of milk, fruits and cereals was associated with more favorable tHcy levels, while the intake of milk and fruits with more favorable plasma B2 levels. However, these findings need to be further confirmed from controlled dietary intervention studies examining the modulation of biomarkers of B-vitamins.

Protein N-linked homocysteine is associated with recurrence of venous thromboembolism

BackgroundRecently, protein N-linked homocysteine (Hcy) has been measured in healthy subjects and patients with marked hyperhomocysteinemia. Since elevated total Hcy (tHcy) levels are associated with increased risk of venous thromboembolism (VTE), we aimed to investigate protein N-linked Hcy levels in patients with VTE. MethodsWe studied 200 consecutive patients with VTE (89 men, 111 women, aged from 17 to 83years), including 57 subjects with a subsequent episode of VTE (recurrent VTE) during 24months of follow-up. Protein N-linked Hcy was assayed using high-performance liquid chromatography with an on-column derivatization with o-phthaldialdehyde and fluorescence detection. ResultsThe median protein N-linked Hcy was 1.404μM (interquartile range [IQR] 0.859–2.066), while the median tHcy (IQR) was 9.1μM (6.8–11.2). In the whole group protein N-linked Hcy correlated only with C-reactive protein (CRP; r=0.44, p<0.0001). In patients with recurrent VTE protein N-linked Hcy correlated with C-reactive protein (r=0.43, p<0.0001), tHcy (r=0.42, p=0.001) and age (r=0.32, p=0.014), but not with thrombophilia, unprovoked VTE or the current anticoagulation. Hyperhomocysteinemia, defined as tHcy ≥15μM (n=14.7%), was not associated with higher protein N-linked Hcy. Patients with recurrent VTE had higher levels of protein N-linked Hcy compared to those who experienced a single episode of VTE (1.553μM, 1.157–2.445 vs. 1.27μM, 0.826–1.884; p=0.002). Multiple regression adjusted for potential confounders showed that the only independent predictor of protein N-linked Hcy in the upper quartile was CRP >3mg/L (odds ratio 3.04, 95% confidence interval 2.12–4.36, p<0.0001). ConclusionElevated protein N-linked Hcy concentrations, indicating enhanced protein homocysteinylation in vivo, characterize patients with recurrent VTE and this phenomenon is associated with enhanced inflammatory state.

Elevated Total Homocysteine Levels in Acute Ischemic Stroke Are Associated With Long-Term Mortality.

Background and Purpose—Total homocysteine (tHcy) levels are associated with secondary vascular events and mortality after stroke. The aim of this study was to investigate whether tHcy levels in the acute phase of a stroke contribute to the recurrence of cerebro-cardiovascular events and mortality.Methods—A total of 3799 patients were recruited after hospital admission for acute ischemic stroke. Levels of tHcy were measured within 24 hours after primary admission. Patients were followed for a median of 48 months.Results—During the follow-up period, 233 (6.1%) patients died. After adjustment for age, smoking status, diabetes mellitus, and other cardiovascular risk factors, patients in the highest tHcy quartile (>18.6 μmol/L) had a 1.61-fold increased risk of death (adjusted hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.03–2.53) compared with patients in the lowest quartile (≤10 μmol/L). Further subgroup analysis showed that this correlation was only significant in the large-artery atherosclerosis stroke subtype (adjusted HR, 1.80; 95% CI, 1.05–3.07); this correlation was not significant in the small-vessel occlusion subtype (adjusted HR, 0.80; 95% CI, 0.30–2.12). The risk of stroke-related mortality was 2.27-fold higher for patients in the third tHcy quartile (adjusted HR, 2.27; 95% CI, 1.06–4.86) and 2.15-fold more likely for patients in the fourth quartile (adjusted HR, 2.15; 95% CI, 1.01–4.63) than for patients in the lowest tHcy quartile. The risk of cardiovascular-related mortality and the risk of recurrent ischemic stroke were not associated with tHcy levels.Conclusions—Our findings suggest that elevated tHcy levels in the acute phase of an ischemic stroke can predict mortality, especially in stroke patients with the large-vessel atherosclerosis subtype.

Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR C677T mutation in type 2 diabetic outpatients taking metformin.

Hyperhomocysteinemia and vitamin B12 deficiency may be involved in the development of diabetic peripheral neuropathy (DPN). Metformin therapy may reduce vitamin B12 plasma levels, thus contributing to DPN. The purposes of this cross-sectional study were to assess (1) the potential associations of DPN with serum levels of homocysteine (tHcy), B-vitamins, and/or the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation; (2) the influence of chronic treatment with metformin on tHcy and B-vitamins concentrations and, finally, (3) to evaluate whether, by this influence, metformin is a risk factor for DPN in a group of type 2 diabetic outpatients. Our data showed that fasting tHcy, folate, and vitamin B12 levels and the MTHFR C677T genotype distribution were comparable between subjects with (n = 79, 30 %) and without DPN (n = 184, 70 %). Metformin-treated subjects (n = 124, 47 %) showed significantly lower levels of vitamin B12 (P < 0.001), but the prevalence of DPN was not different when compared to those not treated with this drug (33 vs. 27 %, P = NS). At univariate regression analysis, DPN was associated with age, duration of diabetes, HbA1c, creatinine levels, and the presence of coronary heart disease (CHD), and negatively with HDL-C concentrations (P < 0.05 all), but at multivariate regression analysis, high creatinine levels (P = 0.06), low HDL-C levels (P = 0.013), and a higher prevalence of CHD (P = 0.001) were the only variables independently associated with DPN in this population. In conclusion, in these type 2 diabetic outpatients circulating levels of tHcy, folate, and the MTHFR C677T mutation are not associated with DPN, which was predicted by creatinine levels, CHD, and dyslipidemia. Metformin therapy is associated with a mild vitamin B12 level reduction, but not with DPN.

Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice.

Cystathionine beta synthase (CBS) deficiency is a recessive inborn error of metabolism characterized by elevated serum total homocysteine (tHcy). Betaine supplementation, which can lower tHcy by stimulating homocysteine remethylation to methionine, is often given to CBS deficient patients in combination with other treatments such as methionine restriction and supplemental B-vitamins. However, the effectiveness of betaine supplementation by itself in the treatment of CBS deficiency has not been well explored. Here, we have examined the effect of a betaine supplemented diet on the Tg-I278T Cbs (-/-) mouse model of CBS deficiency and compared its effectiveness to our previously published data using a methionine restricted diet. Tg-I278T Cbs (-/-) mice on betaine, from the time of weaning until for 240days of age, had a 40% decrease in mean tHcy level and a 137% increase in serum methionine levels. Betaine-treated Tg-I278T Cbs (-/-) mice also exhibited increased levels of betaine-dependent homocysteine methyl transferase (BHMT), increased levels of the lipogenic enzyme stearoyl-coenzyme A desaturase (SCD-1), and increased lipid droplet accumulation in the liver. Betaine supplementation largely reversed the hair loss phenotype in Tg-I278T Cbs (-/-) animals, but was far less effective than methionine restriction in reversing the weight-loss, fat-loss, and osteoporosis phenotypes. Surprisingly, betaine supplementation had several negative effects in control Tg-I278T Cbs (+/-) mice including decreased weight gain, lean mass, and bone mineral density. Our findings indicate that while betaine supplementation does have some beneficial effects, it is not as effective as methionine restriction for reversing the phenotypes associated with severe CBS deficiency in mice.

Homocysteine and the risk of age-related macular degeneration: a systematic review and meta-analysis.

Contrasting results have been reported regarding the associations between plasma total homocysteine (tHcy) and B vitamin levels and age-related macular degeneration (AMD) risk. Thus, we aimed to systematically evaluate these associations. Relevant case control studies in English were identified via a thorough search of the PubMed, Medline, and Embase databases from inception to June 2014. The results were pooled using Review Manager 5.2.1. Eleven studies (including 1072 cases and 1202 controls) were eligible for analysis of tHcy levels; additionally, 3 studies (including 152 cases and 98 controls) were eligible for analysis of folic acid and vitamin B12 levels. The cumulative results demonstrated that the plasma tHcy level among the AMD cases was 2.67 μmol/L (95% confidence interval [CI], 1.60-3.74) higher than that among the controls. In contrast, the vitamin B12 level among the AMD cases was 64.16 pg/mL (95% CI, 19.32-109.00) lower than that among the controls. Subgroup analyses showed that the folic acid level was 1.66 ng/mL (95% CI, 0.10-3.21) lower for the wet type. Together, the results demonstrated that AMD is associated with elevated tHcy levels and decreased vitamin B12 levels. Plasma tHcy may act as a modulator of the risk for AMD based on the current evidence.

Associations between plasma total homocysteine, blood pressure stages and pulse wave velocity in Chinese rural community population

The aim of the study was to examine the associations among plasma total homocysteine (tHcy) and blood pressure (BP) stages and brachial–ankle pulse wave velocity (ba-PWV) in a Chinese rural community population. In this cross-sectional study, 2148 rural community subjects with normotension and mild hypertension (HTN) were classified into four groups according to ba-PWV level. Multivariate regression showed that ba-PWV was significantly and independently correlated with tHcy (β = 5.32, p < 0.001) in the entire study population. Moreover, ba-PWV showed a significant increase with increasing plasma tHcy level in subjects with both high normal BP and grade 1 HTN (p < 0.05). Compared with optimal BP stage, ba-PWV was significantly associated with high normal BP stage (β = 193, p < 0.001) and grade 1 HTN (β = 413, p < 0.001).There was a statistical interaction effect between high normal BP stage and optimal BP stage (p = 0.045). The similar result was found between subjects with optimal BP and those with grade 1 HTN (p = 0.037). In conclusion, tHcy was independently correlated with ba-PWV in subjects with high normal BP and grade 1 HTN. High normal BP and grade 1 HTN may worsen the impact of tHcy on arterial stiffness in a Chinese rural community population.

Homocysteine, Ischemic Stroke, and Coronary Heart Disease in Hypertensive Patients

Total homocysteine level (tHcy) is a risk factor of ischemic stroke (IS) and coronary heart disease. However, the results are conflicting and mainly focused on healthy individuals in developed countries. A prospective, population-based cohort study was conducted among 5935 participants from 60 communities in the city of Shenzhen, China. A Cox regression analysis was applied to evaluate the contribution of tHcy to the risk of IS and coronary heart disease. The effect of folic acid supplementation on tHcy levels was also evaluated among 501 patients with essential hypertension, who received an average of 2.5 years of folic acid supplementation. After adjustment for confounding factors, the hazard ratios (95% confidence intervals) of IS caused by hyperhomocysteinemia were 2.18 (1.65-2.89), 2.40 (1.56-3.67), and 2.73 (1.83-4.08) in the total, male, and female participants, respectively. Compared with normal levels of tHcy (<15 μmol/L), the hazard ratios (95% confidence intervals) for IS in the highest tHcy category (≥30 μmol/L) were 4.96 (3.03-8.12), 6.11 (3.44-10.85), and 1.84 (0.52-6.46) in the total, males, and females participants, respectively. However, we did not observe a significant relationship between tHcy and the risk of coronary heart disease. The 2.5 years of folic acid supplementation reduced tHcy levels by 6.7 μmol/L (27.92%) in patients with essential hypertension. Hyperhomocysteinemia in Chinese hypertensive patients is significantly associated with IS risk but not coronary heart disease susceptibility, and folic acid supplementation can efficiently reduce tHcy levels.

Plasma Homocysteine is a Predictive Factor for Arterial Stiffness: A Community-Based 4.8-Year Prospective Study.

The authors investigated whether plasma total homocysteine (tHcy) is a predictive factor for arterial stiffness (carotid-femoral pulse wave velocity [cf-PWV] and carotid-radial PWV) in 1447 patients from a 4.8-year prospective study in Beijing, People's Republic of China. Baseline tHcy showed a significant relationship with follow-up cf-PWV (β=0.817, P=.015) in a multivariable linear regression analysis. A stepwise logistic regression model showed that baseline levels of tHcy were significantly associated with follow-up cf-PWV in the adjusted models. Furthermore, the baseline tHcy levels showed a significant association with increases in cf-PWV. There was no association between the change in tHcy and increase in PWV. The present study clearly demonstrated an association between tHcy levels and arterial stiffness, indicating that tHcy is an independent predictive factor for arterial stiffness in a community-based population.

Interactions between plasma homocysteine and arterial stiffness in chronic kidney disease in community-dwelling individuals: The Maine-Syracuse Study.

Plasma homocysteine (tHcy) is associated with kidney disease. However, few, if any, studies have examined homocysteine in relation to arterial stiffness, with stratification by the presence or absence of early-stage chronic kidney disease (CKD). The aim of this study was to examine prospective associations between tHcy and carotid-femoral pulse wave velocity (PWV) in persons with and without early-stage CKD in a sample of community-living individuals free from end-stage renal disease, dialysis, stroke and dementia. We conducted a prospective study with 498 participants of the Maine-Syracuse Longitudinal Study (mean age 61 years). Levels of tHcy were positively related to PWV measured 4-5 years later for participants with early-stage CKD (estimated glomerular filtration rate <60 ml min(-1) per 1.73 m(2)). Statistical adjustment was made for multiple confounders, including demographic factors, PWV-related variables and cardiovascular risk factors (b=4.27, 95% confidence interval: 0.23-8.31, P=0.04). These associations were not observed in persons free from CKD. Plasma tHcy is an important predictor of arterial stiffness, as indexed by PWV, in community-living individuals with modest CKD.

Cyclic supplementation of 5-MTHF is effective for the correction of hyperhomocysteinemia

Folic acid supplementation is the mainstay treatment of hyperhomocysteinemia (HHcy). However, no recommendations are currently available in regard to the optimal replacement therapy. Therefore, this prospective study hypothesized that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-methyltetrahydrofolate (5-MTHF) would reduce plasma levels of fasting total homocysteine (tHcy) in patients with mild/moderate HHcy. Patients with a new diagnosis of mild/moderate HHcy were evaluated for the methylenetetrahydrofolate reductase genotype and the presence of major features of metabolic syndrome. All enrolled subjects received a cyclic 5-MTHF oral supplementation and were reevaluated after each treatment cycle for a total of 2 years. In the 246 enrolled subjects, a significant reduction of tHcy levels occurred after the first cycle of treatment (from 31.6 ± 13.6 to 14.4 ± 5.77 μmol/L, P < .001) and during the whole 2-year follow-up (from 31.6 ± 13.6 to 12.18 ± 3.03 μmol/L, P < .001). The values of tHcy returned to reference range in 117 subjects (51.3%) after the first cycle and in 198 (86.8%) during the follow-up. The risk of failure in tHcy level normalization was increased in patients with metabolic syndrome (hazard ratio [HR], 3.49; 95% confidence interval [CI], 1.46-8.36), higher baseline tHcy levels (HR, 1.045; 95% CI, 1.018-1.073), or methylenetetrahydrofolate reductase homozygous mutation (HR, 6.59; 95% CI, 2.64-16.4). This study clearly shows that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-MTHF supplementation is able to significantly reduce tHcy levels in patients with mild/moderate HHcy.

Abstract W P398: PFO Closure Reduces High Homocysteine Level in Atrial Blood of Stroke Patients

Background: PFO allows venous clots to bypass pulmonary filtration, leading to strokes. We previous found in metabolite screening that PFO endovascular closure lower markers of oxidative stress and homocysteine levels in peripheral venous blood. Here we study changes of homocysteine during endovascular closure in cardiac atrial blood to better understand the central metabolism of PFO in circulation. Method: PFO stroke patients are propectively recruited according to IRB approval with plasma sampled from left (LA) and right (RA) atria pre- and post- PFO closure (n=97). Total homocysteine (tHCY) level was measured by selected reaction monitoring using mass spectrometry. Result: tHCY level decreased significantly in both RA and LA post PFO closure (Fig. 1A, p = 0.0014; RA: reduced by 8.54% Fig. 1B, p = 0.0304; LA: reduced by 9.90% Fig. 1C, p = 0.0470). Notably, tHCY reduction was skewed towards patients with higher tHCY levels before PFO closure (Fig. 1D and E, Kolmogorov-Smirnov test, RA: p = 0.0413; LA: p = 0.0010), such that more patients with higher tHCY level had a more significant reduction in tHCY levels compared to those with lower/normal levels. Conclusion: We found that PFO closure efficiently reduced tHCY level in both venous and arterial systems of stroke patients with high tHCY level. This effect is more pronounced in patients with higher levels suggesting PFO closure may help change the pathophysiology of hyperhomocysteinemia; further studies are ongoing to understand the underlying mechanism.

Abstract 224: Increased Total Homocysteine Levels Are Associated With the Risk of Dementia Independently of Cerebral Small-vessel Disease

Objectives: Increased serum total homocysteine (tHcy) levels have been associated with not only vascular injury but also dementia. However, given an association between Hcy and vascular injury, such as cerebral small-vessel disease (SVD) or renal impairment, to what extent Hcy would impact future dementia beyond these confouders is unknown. We assessed the predictive value of tHcy levels with the risk of dementia in patients with vascular risk factors, when controlling for the MRI-findings and renal imapirment. Methods: Within a Japanese cohort of partients with vascular risk factors in an observational study from 2001, we evaluated the association between tHcy levels at baseline, defined as a continuous variable (per 1 μmol/L) and as a categorical variable (the tertile of tHcy), the prevalence of MRI-findings, and incident all-cause dementia during follow-up. Baseline brain MRI was used to determine SVD (lacuna, white matter hyperintensities and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy). Cox proportional hazards analyses were performed for predictors of dementia adjusting for age, sex, APOEε4 allele, educational level, cerebrovascular events, estimated glomerular filtration rate (eGFR), vascular risk factors, and MRI-findings. Results: Of the 643 subjects (mean:67.2±8.4years, male:59%, 12.9±2.6years of schooling), in multivariable analyses adjusted for age, sex, hypertension, cerebrovascular events, eGFR, and intima-media thickness, the highest tHcy tertile (vs lowest) were associated with lacuna, CMBs and strictly deep CMBs, respectively. During the mean 7.3-year follow-up (range:3-13), 47 incident dementia patients (Alzheimer’s disease:24; vascular dementia:18; mixed-type:3; other:2) were diagnosed. In multivariable analyses adjusted for age, sex, cerebrovascular events, eGFR, and MRI-findings, tHcy level or the highest tertile of tHcy for all-cause dementia remained significant, respectively (relative risk [RR]1.09: p=0.02, RR;2.59: p=0.021). Conclusions: Our results provide additional evidence of Hcy that leads to increased susceptibility to the risk of dementia, suggesting that this association may be mediated by independent mechanisms.

Hyperhomocysteinemia and MTHFR polymorphisms as antenatal risk factors of white matter abnormalities in two cohorts of late preterm and full term newborns.

Higher total homocysteine (tHcy) levels, and C677T and A1298C methylenetetrahydrofolate (MTHFR) polymorphisms, have been reported in preterm or full term newborns with neonatal encephalopathy following perinatal hypoxic-ischemic insult. This study investigated the causal role of tHcy and MTHFR polymorphisms together with other acquired risk factors on the occurrence of brain white matter abnormalities (WMA) detected by cranial ultrasound scans (cUS) in a population of late preterm and full term infants. A total of 171 newborns (81 M, 47.4%), 45 (26.3%) born <37 wks, and 126 (73.7%) born ≥37 wks were recruited in the study. cUS detected predominant WMA pattern in 36/171 newborns (21.1%) mainly characterized by abnormal periventricular white matter signal and mild-to-moderate periventricular white matter volume loss with ventricular dilatation (6/36, 16.6%). WMA resulted in being depending on tHcy levels (P < 0.014), lower GA (P < 0.000), lower Apgar score at 1 minutes (P < 0.000) and 5 minutes (P < 0.000), and 1298AC and 677CT/1298AC genotypes (P < 0.000 and P < 0.000). In conclusion, both acquired and genetic predisposing antenatal factors were significantly associated with adverse neonatal outcome and WMA. The role of A1298C polymorphism may be taken into account for prenatal assessment and treatment counseling.

Elevated total plasma homocysteine levels are associated with type 2 diabetes in women with hypertension.

There is only limited available evidence of a relationship between total plasma homocysteine (tHcy) levels and type 2 diabetes in hypertensive subjects. A total of 5,935 Chinese essentially hypertensive subjects were recruited by cluster sampling from 60 communities. The cases had diabetes, whereas the controls did not. Anthropometric indices and biochemical parameters were assessed using standard procedures. A multivariable analysis was performed to analyze the association of tHcy and type 2 diabetes susceptibility in hypertensive subjects. The 5,241 controls (women/men: 2,716/2,625) and 594 cases (women/men: 291/303) were recruited consecutively. The level of tHcy was dose- dependently associated with type 2 diabetes in the hypertensive women subjects. After controlling for corresponding confounding factors, a significant trend was only noted in the women subjects, with odds ratios per 5 μmol/L tHcy of 1.11 (95% confidence interval (CI), 1.07-1.16) in the crude model, 1.05 (95% CI, 1.01-1.11) in model 1, and 1.07 (95% CI, 1.02-1.13) in model 2. However, no significant result was found for levels of tHcy>or=15 μmol/L vs <15 μmol/L in the men, women and all hypertensive subjects. When the level of tHcy was divided into quartiles, tHcy was positively associated with type 2 diabetes in hypertensive women subjects. However, when the level of tHcy was separated into hyperhomocysteinemic (>or=15 μmol/L) and normal (<15 μmol/L), no significant results were observed.

Impact of MTHFR (C677T) gene polymorphism on antiepileptic drug monotherapy in North Indian epileptic population.

BACKGROUND AND OBJECTIVESAntiepileptic drugs (AEDs) are known to interfere with homocysteine metabolism. Hyperhomocysteinemia may be a risk factor associated in the long-term treatment with AEDs. Both genetic and non-genetic factors are responsible for hyperhomocysteinemia. MTHFR C677T. Polymorphism leads to the reduction in enzyme activity and subsequent elevation of plasma homocysteine. This study aimed to investigate the role of MTHFR C677T polymorphism in epileptic patients receiving AEDs as monotherapy (phenytoin, carbamazepine, and sodium valproate) and showing toxicity and non-toxicity, and the impact of AEDs on hyperhomocysteinemia in North Indian population.DESIGN AND SETTINGSBlood samples for this case-control study were collected from the outpatient department and wards of the Department of Neurosciences at the All India Institute of Medical Sciences, New Delhi, India, between July 2008 and May 2010.PATIENTS AND METHODSIn this study, 200 epileptic patients and 100 normal controls were assessed for total homocysteine (tHcy), vitamin B12, and folate levels using enhanced chemiluminescence enzyme immunoassay method (ImmuliteR, 1000 systems, DPC, United States); genotyping of MTHFR C677T was done using polymerase chain reaction-restriction fragment length polymorphism method.RESULTSThe results showed a significant increase in tHcy levels in epileptic patients with toxicity and non-toxicity than in normal controls (P<.005). The allelic and genotypic distributions were found to be statistically significant in toxicity and non-toxicity groups (P<.05).CONCLUSIONThe result confirmed that hyperhomocysteinemia is common in adults receiving AED treatment for epilepsy with toxicity and non-toxicity groups. This increase in tHcy is mainly related to low folate and vitamin B12 levels, which are the main determinants for tHcy.