Association of Elevated Plasma Total Homocysteine With Dementia With Lewy Bodies: A Case-Control Study

Background: Elevated plasma total homocysteine (tHcy) level, a known risk factor for vascular disease, is reported to be an independent risk factor for cognitive impairment and Alzheimer’s disease (AD) in most studies. tHcy may also be associated with dementia with Lewy bodies (DLB).Objective: To investigate the association between plasma tHcy levels and DLB or AD.Methods: This is a case-control study including 132 DLB patients, 264 AD patients, and 295 age-matched healthy controls. We used multivariate logistic regression model to analyze the data with adjustments for confounding variables.Results: The highest tHcy tertile (>13.9 μmol/L) was significantly independently associated with DLB [adjusted odds ratio (OR): 4.65, 95% confidence interval (CI): 1.95–11.10, P = 0.001] and AD (adjusted OR: 1.82, 95% CI: 1.02–3.23, P = 0.041) compared to the lowest tertile (<10.7 μmol/L). The cumulative frequency plots showed a shift in the distribution of the tHcy concentrations to higher values in patients with DLB compared to AD. The mean tHcy levels were stable and not altered by the duration of cognitive impairment prior to the collection of blood samples from DLB patients.Conclusion: Elevated plasma tHcy levels were independently associated with DLB, and the association was stronger for DLB than for AD. The lack of a relationship between tHcy levels and symptom duration may refute these observed associations being a consequence of DLB, and future longitudinal studies will be required to confirm whether tHcy plays a causative role in DLB.

Plasma Homocysteine Is a Predictive Factor for Accelerated Renal Function Decline and Chronic Kidney Disease in a Community-Dwelling Population

<b><i>Background:</i></b> Whether elevated plasma total homocysteine (tHcy) is a risk factor for the progression of kidney disease in general population has not been well established. The purpose of this study was to investigate the prognostic properties of plasma tHcy for renal function decrement and early chronic kidney disease (CKD) in community-dwelling populations with normal renal function at baseline. <b><i>Methods:</i></b> A total of 1,426 participants were enrolled and followed for a median of 4.8 years (interquartile range, 4.5–5.2), and estimated glomerular filtration rate (eGFR) was evaluated. One main outcome was the rapid eGFR decline defined as a decline in eGFR of &#x3e;3 mL/min per 1.73 m² per year; the other was the new incidence of CKD. <b><i>Results:</i></b> At the end of follow-up, the incidence of rapid eGFR decline and new-onset CKD was 20.7 and 5.6%, respectively. In multivariate linear regression analysis, age, central pulse pressure, fasting blood glucose, and concentration of tHcy were independent determinants of the change in eGFR. There was a graded association between tHcy quartiles and eGFR decline. Compared with participants with the lowest quartile of tHcy levels, those with the highest quartile had significantly increased risk for rapid eGFR decline (adjusted odds ratio [aOR] = 1.81; 95% confidence interval [CI]: 1.25–2.94) and new onset of CKD (adjusted hazard ratio = 4.29; 95% CI: 1.42–12.99) after adjusting for various confounders. Similarly, significant associations were also found when baseline tHcy was classified as hyperhomocysteinemia (&#x3e;15 μmol/L) versus normal tHcy level (≤15 μmol/L). However, there was only association between the change in tHcy levels and new occurrence of CKD but not with rapid eGFR decline (aOR = 0.99, <i>p</i> = 0.613). <b><i>Conclusions:</i></b> In this prospective cohort of individuals from community-based population, elevated plasma tHcy emerged as an independent predictor of renal function decline and incident CKD, which might support selection of at-risk individuals.

The correlation between plasma total homocysteine level and gestational diabetes mellitus in a Chinese Han population

To assess the correlation between plasma total homocysteine (tHcy) level and gestational diabetes mellitus (GDM) in a Chinese Han population. This case–control study included 350 GDM patients and 346 gestational week-matched normal glucose tolerance (NGT) pregnant women. Plasma tHcy and insulin levels were analyzed by HPLC and ELISA respectively. Logistic regression analysis was used to investigate the correlation between plasma tHcy level and risk of GDM. Women with GDM had a higher plasma tHcy level than NGT women (6.61 ± 1.32 vs. 6.17 ± 1.29 μmol/L, P = 0.001)). The GDM risk was 1.79 (OR = 1.79, 95% CI 1.18–2.72, P = 0.006) times higher in women whose plasma tHcy level was ≥ 7.29 μmol/L compared to women with plasma tHcy level < 5.75 μmol/L. Stratified analysis showed the GDM risk were much higher when HOMA-IR index ≥ 2 (OR = 5.42, 95% CI 2.51–11.74, P < 0.001), age ≥ 30 years (OR = 5.14, 95% CI 2.78–9.52, P < 0.001), or women with a family history of type 2 diabetes mellitus (T2DM) (OR = 4.13, 95% CI 1.78–9.56, P = 0.001). In the Chinese Han population, an elevated plasma tHcy level may increase the overall risk of GDM especially in women with a high HOMA-IR index, increasing age or with family history of T2DM.

Association between plasma total homocysteine level within normal range and bone mineral density in adults

Background Growing evidence indicates that homocysteine is a noteworthy marker for general health status. However, research regarding plasma total homocysteine (tHcy) levels and bone mineral density (BMD) is sparse and controversial. Hence, we aimed to investigate the association between plasma tHcy level within normal range and lumbar BMD in adults. Methods In this cross-sectional study, using the National Health and Nutrition Examination Survey database, data on 10748 adults aged between 30 and 85 years were analyzed. The weighted multiple logistic regression analyses were conducted to evaluate the association between plasma tHcy level and lumbar BMD. The fitted smoothing curves were performed to explore potential non-linear relationships. When non-linearity was detected, we further calculated the inflection point using a recursive algorithm and constructed a weighted two-piecewise linear regression model. Results After adjusting for all the covariates, the association between plasma tHcy and lumbar BMD was different in various age groups (adults aged 30–49 years: β = −0.0004, 95% CI −0.0025, 0.0018; adults aged 50–69 years: β = 0.0001, 95% CI −0.0025, 0.0026; adults aged 70–85 years: β = 0.0050, 95% CI 0.0008, 0.0092). In the subgroup analysis stratified by gender, this association also differed based on gender. There was a negative trend in females (aged 30–49 years: β = −0.0022, 95% CI −0.0054, 0.0011; aged 50–69 years: β = −0.0028, 95% CI −0.0062, 0.0007), and a positive trend in males (aged 30–49 years: β = 0.0018, 95% CI −0.0012, 0.0048; aged 50–69 years: β = 0.0027, 95% CI −0.0009, 0.0063) in both 30–49 years group and 50–69 years group. In the 70–85 years group, this association was significantly positive in males (β = 0.0136, 95% CI 0.0068, 0.0204), but was not significantly different in females (β = 0.0007, 95% CI −0.0046, 0.0060). Conclusion The correlation between plasma tHcy level within the normal range and lumbar BMD differs by age and gender.

Prevalence of Vitamin B-12 Deficiency in US Adults Using the Combined Indicator of Vitamin B-12 status, cB12

Objectives High blood methylmalonic acid (MMA) and homocysteine (tHcy) and low serum B-12 and holotranscobalamin (holoTC) concentrations indicate vitamin B-12 deficiency. The diagnosis is often contradictory when using any test independently. A mathematical model including all 4 biomarkers, named combined indicator of vitamin B-12 status (cB12), has been proposed. Our goal was to describe cB12 in US adults and estimate the prevalence of low or transitional vitamin B-12 status compared to conventional single biomarkers. Methods We assessed cB12 in persons ≥20 y participating in NHANES from 1999 to 2004 from 3 biomarkers: serum vitamin B-12, MMA, and plasma tHcy. Results The following groups had significantly lower cB12: persons ≥70 y compared with younger age groups, males compared with females, non-Hispanic whites compared with non-Hispanic blacks and Mexican Americans, and non-users of vitamin B-12 containing supplements compared with users. Shorter fasting times and impaired renal function also resulted in lower cB12. There was a strong significant association of cB12 with serum vitamin B-12 (Spearman r = 0.75), MMA (r = −0.70), and tHcy concentrations (r = −0.59). The prevalence of vitamin B-12 deficiency varied with the biomarker and cutoff used: 2.2% and 13% for serum vitamin B-12 &lt; 148 and 148 − 222 pmol/L, respectively; 6.0% for MMA exceeding an age-specific cutoff between 250 and 320 nmol/L; and 8.4% for tHcy &gt; 13 μmol/L. Using the proposed cB12 cutoff of &lt; −0.5, 2.7% of adults had “low or transitional vitamin B-12 status”. Conclusions Based on the new combined indicator using 3 biomarkers a larger portion of US adults had adequate vitamin B-12 status (97%) compared to conventional single biomarkers (between 85% and 94%), likely indicating the higher specificity of cB12. It is unclear whether the availability of holoTC data would change these findings. Funding Sources This work was supported by direct appropriations from US Congress.

The risk association of plasma total homocysteine with acute myocardial infarction is modified by serum vitamin A

Background Plasma total homocysteine (tHcy) has been implicated in the development of cardiovascular disease, but the mechanisms remain unclear. Vitamin A (Vit-A) is involved in homocysteine metabolism and we therefore explored the potential interaction between plasma tHcy and serum Vit-A in relation to incident acute myocardial infarction. Methods Cox proportional hazards models were used to assess the prospective relationships between tHcy and acute myocardial infarction in 2205 patients from Western Norway undergoing elective coronary angiography for suspected stable angina pectoris. Results are reported as hazard ratio per standard deviation increase in log-transformed tHcy. An interaction term for tHcy × Vit-A was added to multivariate models including age, sex, smoking, apolipoprotein B fasting, statin and aspirin prescription and estimated glomerular filtration rate. Results Geometric mean (geometric standard deviation) age of the participants (64.3% men) was 62.3 (1.24) years. Plasma tHcy was higher among participants in the upper versus lower Vit-A tertile. During 7 (2.4) years of follow-up, 15.1% suffered an AMI. A significant association of plasma tHcy with AMI in the total study population was observed. When we stratified the population according to Vit-A tertiles, plasma tHcy was associated with acute myocardial infarction only in the upper Vit-A tertile (hazard ratio per SD: 1.25, 95% confidence interval: 1.04–1.53, pinteraction = 0.03). Conclusions The risk relationship between plasma tHcy and acute myocardial infarction was modified by serum concentrations of Vit-A in patients with suspected stable angina pectoris. This finding may clarify the relationship between tHcy and cardiovascular disease.

INCREASED HOMOCYSTEINE PLASMA LEVELS IN BREAST CANCER PATIENTS OF A MEXICAN POPULATION

Aim: Hyperhomocysteinemia has been associated with different pathologies, including cardiovascular diseases, hypertension, diabetes, and breast cancer (BC). To examine the differences in total homocysteine (tHcy) plasma levels, we compared healthy women to BC patients from a Mexican population. Materials and Methods: The tHcy plasma levels were measured using high-performance liquid chromatography with a fluorescence detector in 89 female controls and 261 BC patients. Results: The observed plasma tHcy levels were significantly higher among the BC patients (11.1019 ± 5.9161 µmol/l) compared to the controls (9.1046 ± 1.3213 µmol/l) (p = 0.002), and these differences were evident when stratified by age (≥ 50 years old), menopause status, overweight and obesity, miscarriages, node metastases, progression, subtype classification (luminal, Her2 and triple negative) and nonresponse to chemotherapy. Conclusions: The tHcy plasma levels could be a good marker for the progression and chemosensitivity of BC in the analyzed sample from a Mexican population.

Methionine Metabolites in Patients With Sepsis

Objective: Sepsis is characterized by microvascular dysfunction and thrombophilia. Several methionine metabolites may be relevant to this sepsis pathophysiology. S-adenosylmethionine (SAM) serves as the methyl donor for trans-methylation reactions. S-adenosylhomocysteine (SAH) is the by-product of these reactions and serves as the precursor to homocysteine. Relationships between plasma total homocysteine concentrations (tHcy) and vascular disease and thrombosis are firmly established. We hypothesized that SAM, SAH, and tHcy levels are elevated in patients with sepsis and associated with mortality. Methods: This was a combined case–control and prospective cohort study consisting of 109 patients with sepsis and 50 control participants without acute illness. The study was conducted in the medical and surgical intensive care units of the University of Rochester Medical Center. Methionine, SAM, SAH, and tHcy concentrations were compared in patients with sepsis versus control participants and in sepsis survivors versus nonsurvivors. Results: Patients with sepsis had significantly higher plasma SAM and SAH concentrations than control participants (SAM: 164 [107-227] vs73 [59-87 nM], P < .001; SAH: 99 [60-165] vs 35 [28-45] nM, P < .001). In contrast, plasma tHcy concentrations were lower in sepsis patients compared to healthy control participants (4 [2-6]) vs 7 [5-9] μM; P = .04). In multivariable analysis, quartiles of SAM, SAH, and tHcy were independently associated with sepsis ( P = .006, P = .05, and P < .001, respectively). Sepsis nonsurvivors had significantly higher plasma SAM and SAH concentrations than survivors (SAM: 223 [125-260] vs 136 [96-187] nM; P = .01; SAH: 139 [81-197] vs 86 [55-130] nM, P = .006). Plasma tHcy levels were similar in survivors vs nonsurvivors. The associations between SAM or SAH and hospital mortality were no longer significant after adjusting for renal dysfunction. Conclusions: Methionine metabolite concentrations are abnormal in sepsis and linked with clinical outcomes. Further study is required to determine whether these abnormalities have pathophysiologic significance.

Efficacy of Methylcobalamin to Normalise Elevated Homocysteine of Vitamin B12 Deficient Vegetarians: A Double Blind Placebo Control Study

Vegetarians are known to be deficient in vitamin B12, due to a lack of dietary animal products, which can elevate plasma total homocysteine (tHcy). Elevated total tHcy can render vegetarians susceptible to cardiovascular disease (CVD). There are a limited number of published studies in relation to the efficacy of methylcobalamin to normalise plasma tHcy of vitamin B12 deficient vegetarians. The primary objective of the present study was to explore the relationship between supplementary oral methylcobalamin and levels of tHcy of vitamin B12 deficient vegetarians; to reduce the risk of developing primary CVD. A randomised double blind placebo controlled pilot study was conducted to monitor and analyse baseline and post treatment levels of plasma tHcy, 49 volunteer vegetarians were recruited to participate in this study. Statistical analysis employing SPSS software indicated that methylcobalamin reduced mean baseline plasma tHcy of 15.5 µmolL-1 (n=39) to a mean plasma tHcy level of 8.4 µmolL-1 (P < 0.001). In a second group that contained details of ten withdrawn participants, which was conducted on an ‘Intention to Treat’ (ITT) basis, indicated that methylcobalamin was shown to be reduced from a mean baseline plasma tHcy of 14.7 µmolL-1(n=49) to a mean plasma tHcy level of 9.1 µmolL-1 (P < 0.001). The findings of the study have the potential to alert vegetarians of the possible risk of becoming vitamin B12 deficient, and to help avoid the risk of developing homocysteine related CVD. The quality data obtained in the study will allow an accurate sample size to be calculated for a future definite clinical study.

Abstract 272: Hyperhomocysteinemia Potentiated the Impairment of Hydrogen Sulfide-induced Endothelium-derived Hyperpolarization-mediated Vascular Relaxation in Diabetic Db/db Mice

Background: Cumulative evidence indicates that plasma homocysteine (Hcy) level is positively correlated with cardiovascular mortality in Type 2 diabetic patients. Aims: To explore the effects and mechanisms of elevated plasma Hcy level[[Unable to Display Character: &#8213;]] hyperhomocysteinemia (HHcy) on endothelial function in db/db mice. Methods and Results: HHcy was induced in diabetic db/db and non-diabetic db/+ mice fed with a high methionine diet (HM, 2% methionine) for 8 weeks (plasma tHcy=54.31±5.4 and 34.21±4.15 μM). Endothelial function was examined in small mesenteric arteries (SMA) using myographs. In non-diabetic mice, HHcy did not change vascular relaxation to acetylcholine (Ach); whereas, nitric oxide (NO)- and prostacyclin (PGI2)-mediated relaxation to Ach were impaired. Interestingly, endothelium-derived hyperpolarization factor (EDHF)-mediated relaxation to Ach was improved. In diabetic mice, HHcy potentiated the impairment of NO-, PGI2- and EDHF-mediated relaxation to Ach. Moreover, sodium hydrogen sulfide (NaHS), a donor of hydrogen sulfide (H2S), induced EDHF-mediated relaxation which was impaired in diabetic mice and potentiated by HHcy. NS309, a non-specific calcium-activated potassium channel (Kca) activator, significantly improved H2S- and Ach-induced EDHF-mediated relaxation in diabetic mice with HHcy. Tram-34, an intermediate conductance Kca (IK) blocker, but not small conductance Kca blocker apamin, diminished HHcy-induced impairment of EDHF-mediated relaxation in diabetic mice, suggesting that IK inactivation plays a major role. Free sulfide was decreased in plasma and SMA of diabetic mice which was potentiated with HHcy. Superoxide generation was increased and potentiated by HHcy in lung ECs from diabetic mice. Moreover, PEG-SOD improved vascular relaxation in diabetic mice with HHcy. Finally, tyrosine nitration of IK was increased in human cardiac microvascular endothelial cells (ECs) treated with either D-glucose (25 mM) or DL-Hcy (500 μM) for 48h, which was potentiated by a combination of D-glucose and DL-Hcy. Conclusions: H2S is a major EDHF in resistant arteries in mouse. H2S-contributed EDHF-mediated vascular relaxation was impaired in diabetes and was potentiated by HHcy via oxidative stress and IK inactivation.