Effectiveness of B Vitamins and Their Interactions with Aspirin in Improving Cognitive Functioning in Older People with Mild Cognitive Impairment: Pooled Post-Hoc Analyses of Two Randomized Trials.

BACKGROUND AND OBJECTIVES: A randomized placebo-controlled trial found a significant negative interaction between aspirin and B vitamins in cognitive functioning in older people with mild cognitive impairment (MCI). To validate this finding, we pooled data of this trial with that of a similar B-vitamin trial (VITACOG) to examine the effectiveness of B vitamins and their interactions with aspirin in improving global cognitive functioning and slowing brain atrophy in older people with MCI. DESIGN: Pooled post-hoc analyses of two randomized placebo-controlled trials. PARTICIPANTS: In total, 545 older people with MCI were included in the study. INTERVENTION: Placebo or B-vitamin supplements (vitamin B12, folic acid with or without vitamin B6) for 24 months. MEASUREMENTS: The primary outcome was the Clinical Dementia Rating scale-global score (CDR-global). The secondary outcomes were CDR-sum of box score (CDR-SOB), memory Z-score, executive function Z-score, and whole brain atrophy rate. RESULTS: 71 (26.2%) and 83 (30.3%) subjects in the active and placebo group respectively were aspirin users. Overall, B vitamins reduced whole brain atrophy rate significantly (P = 0.003), but did not have significant effect on CDR-global, CDR-SOB, memory and executive function. Aspirin use had significant negative interaction effects on B vitamins in CDR-global and CDR-SOB (Beta = 0.993, P = 0.038, and Beta = 0.583, P = 0.009, respectively), but not in memory or executive function Z-scores. Among aspirin non-users, B-vitamin group subjects had more favourable changes in CDR-global and CDR-SOB (P = 0.019 and 0.057, respectively). B vitamins significantly slowed brain atrophy in aspirin non-users (P = 0.001), but not in aspirin users, though the interaction term was not significant (Beta = 0.192, P = 0.276). CONCLUSION: In older people with MCI, B vitamins had significantly favourable effects on global cognitive functioning and whole brain atrophy rate in those who were not taking aspirin, but not in aspirin users.

Homocysteine - from disease biomarker to disease prevention.

We have reviewed the literature and have identified more than 100 diseases or conditions that are associated with raised concentrations of plasma total homocysteine. The commonest associations are with cardiovascular diseases and diseases of the central nervous system, but a large number of developmental and age-related conditions are also associated. Few other disease biomarkers have so many associations. The clinical importance of these associations becomes especially relevant if lowering plasma total homocysteine by B vitamin treatment can prevent disease and so improve health. Five diseases can at least in part be prevented by lowering total homocysteine: neural tube defects, impaired childhood cognition, macular degeneration, primary stroke, and cognitive impairment in the elderly. We conclude from our review that total homocysteine values in adults of 10 µmol/L or below are probably safe, but that values of 11 µmol/L or above may justify intervention. Homocysteine is more than a disease biomarker: it is a guide for the prevention of disease.

Impact of age, gender and CYP2C9/2C19 genotypes on dose-adjusted steady-state serum concentrations of valproic acid-a large-scale study based on naturalistic therapeutic drug monitoring data.

PURPOSE: Valproic acid (VPA) has an extensive interindividual pharmacokinetic variability. Published data regarding the impact of gender, age, and CYP2C9/2C19 genetics on VPA variability are conflicting, and the purpose of present study is to clarify the effect of these factors on dose-adjusted steady-state serum VPA concentration (C:D ratio) in a large, naturalistic patient material. METHODS: In patients who had been subjected to cytochrome P450 (CYP) genotyping and therapeutic drug monitoring of VPA, information about serum concentrations, dose, gender, age, and CYP2C9/2C19 genotypes was retrospectively collected from a routine TDM database during the period 2008-2012. The effects of age, gender, and CYP2C9/CYP2C19 genotypes on C:D ratios of VPA were investigated by multivariate analyses (mixed model) including sampling time as covariate. RESULTS: In total, 857 serum concentrations from 252 patients were included. A significant gender effect was observed with a 1.3-fold higher estimated C:D ratio in females than in males, i.e., geometric means 0.34 vs. 0.27 µM/mg/day, respectively (p < 0.001). A similar and significant difference in estimated geometric means was found between patients >65 vs. ≤65 years, i.e., 0.36 vs. 0.26 µM/mg/day (p < 0.001), respectively. Finally, no association between the various CYP2C9/2C19 variant genotypes and C:D ratio of VPA was observed (p > 0.1). CONCLUSION: The present study shows that age and gender significantly influence VPA serum concentration. In order to obtain similar drug exposure, our findings suggest that older female patients would generally require 30-50 % lower dosing of VPA compared to younger males. Moreover, we conclude that CYP2C9/2C19 genotype is not relevant for variability in VPA exposure.

Serum S-adenosylmethionine, but not methionine, increases in response to overfeeding in humans.

BACKGROUND: Plasma concentration of the methyl donor S-adenosylmethionine (SAM) is linearly associated with body mass index (BMI) and fat mass. As SAM is a high-energy compound and a sensor of cellular nutrient status, we hypothesized that SAM would increase with overfeeding. METHODS: Forty normal to overweight men and women were overfed by 1250 kcal per day for 28 days. RESULTS: Serum SAM increased from 106 to 130 nmol/l (P=0.006). In stratified analysis, only those with weight gain above the median (high-weight gainers; average weight gain 3.9±0.3 kg) had increased SAM (+42%, P=0.001), whereas low-weight gainers (weight gain 1.5±0.2 kg) did not (Pinteraction=0.018). Overfeeding did not alter serum concentrations of the SAM precursor, methionine or the products, S-adenosyl-homocysteine and homocysteine. The SAM/SAH (S-adenosylhomocysteine) ratio was unchanged in the total population, but increased in high-weight gainers (+52%, P=0.006, Pinteraction =0.005). Change in SAM correlated positively with change in weight (r=0.33, P=0.041) and fat mass (r=0.44, P=0.009), but not with change in protein intake or plasma methionine, glucose, insulin or low-density lipoprotein (LDL)-cholesterol. CONCLUSION: Overfeeding raised serum SAM in proportion to the fat mass gained. The increase in SAM may help stabilize methionine levels, and denotes a responsiveness of SAM to nutrient state in humans. The role of SAM in human energy metabolism deserves further attention.

Association between serum lipids and membrane fatty acids and clinical characteristics in patients with schizophrenia.

OBJECTIVE: Earlier reports indicate that patients with schizophrenia have altered lipid levels in serum and cell membranes. The purpose of this study was to determine the relationship between clinical characteristics and serum and membrane lipids. METHOD: Fifty-five patients with schizophrenia and 51 healthy controls were included. The patients were characterized with Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Functioning (GAF). Serum lipids [high- and low-density lipoprotein cholesterol (HDL, LDL) and triglyceride (TG)] and erythrocyte polyunsaturated fatty acids (PUFA) were measured. RESULTS: Among the participants with schizophrenia, there was a significant correlation between serum triglyceride levels and PANSS-positive symptoms (r = 0.28, P = 0.04), GAF-S (r = -0.48, P = 0.001) and GAF-F (r = -0.32, P = 0.01), and between HDL level and GAF-S (r = 0.37, P = 0.008) and GAF-F (r = 0.28, P = 0.04). Long-chain PUFA were significantly associated with PANSS-negative symptoms (r = 0.52, P < 0.001), GAF-S (r = -0.32, P = 0.02), and GAF-F (r = -0.29, P = 0.04). The patients with schizophrenia had significantly higher TG (P < 0.001) and lower HDL (P < 0.001) levels than healthy controls. HDL was also lower in the subgroup (n = 11) not receiving antipsychotic medication (P = 0.02). CONCLUSION: The results suggest associations between lipid profile and clinical characteristics. This may indicate a role for lipid biology in schizophrenia pathophysiology.

Changes in cognitive function during psychogeriatric treatment in relation to benzodiazepine cessation.

INTRODUCTION: The aim of this study was to investigate cognitive functions after admission to a geriatric psychiatric hospital, and to study the short-term effects of cessation of benzodiazepine use on cognitive functions. METHODS: Details of benzodiazepine use and serum concentration measurements were recorded on admission. The Hopkins verbal learning test, the Stroop test, Digit Vigilance Test and the Mini Mental Status Examination were performed on admission, and after 4 weeks of hospitalization. Test results were compared for the total group of patients, as well as for benzodiazepine "continuers" and the "quitters". RESULTS: For all patients (n=224), improved performances were observed in 10 out of 12 cognitive tests. Significant improvements were seen in 4 out of 12 tests. Benzodiazepine "quitters" improved significantly more than the "continuers" (p=0.027) only on the Hopkins verbal learning test, delayed recall performance. DISCUSSION: Among elderly psychiatric patients, cognitive function improved slightly during the 4 weeks of hospital treatment, but only for one of the memory tests, the improvement was related to the cessation of benzodiazepine treatment.

A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia.

Membrane lipid metabolism and redox regulation may be disturbed in schizophrenia. We examined the clinical effect of adding an omega-3 fatty acid and/or vitamins E+C to antipsychotics. It was hypothesized that lower baseline levels of polyunsaturated fatty acids (PUFAs) would predict more benefit from the add-on treatment. The trial had a multicenter, randomized, double-blind, placebo-controlled 2 × 2 factorial design. Patients aged 18-39 years with schizophrenia or related psychoses were consecutively included at admission to psychiatric departments in Norway. They received active or placebo ethyl-eicosapentaenoate (EPA) 2 g day⁻¹ and active or placebo vitamin E 364 mg day⁻¹+vitamin C 1000 mg day⁻¹ (vitamins) for 16 weeks. The main outcome measures were Positive and Negative Syndrome Scale (PANSS) total and subscales scores, analyzed by linear mixed models. Ninety-nine patients were included. At baseline, erythrocyte PUFA were measured in 97 subjects. Given separately, EPA and vitamins increased drop-out rates, whereas when combined they did not differ from placebo. In low PUFA patients, EPA alone impaired the course of total PANSS (Cohen's d=0.29; P=0.03) and psychotic symptoms (d=0.40; P=0.003), especially persecutory delusions (d=0.48; P=0.0004). Vitamins alone impaired the course of psychotic symptoms (d= 0.37; P=0.005), especially persecutory delusions (d=0.47; P=0.0005). Adding vitamins to EPA neutralized the detrimental effect on psychosis (interaction d=0.31; P=0.02). In high PUFA patients, there were no significant effects of trial drugs on PANSS scales. In conclusion, given separately during an acute episode, EPA and vitamins E+C induce psychotic symptoms in patients with low levels of PUFA. Combined, these agents seem safe.

Plasma sulfur amino acids and stearoyl-CoA desaturase activity in two Caucasian populations.

In rats, dietary restriction of the cysteine precursor methionine suppresses hepatic stearoyl-CoA desaturase (SCD)-1 expression and activity, whereas cysteine supplementation reverses these effects. In 2 independent cohorts: Hordaland Health Study (HUSK; N=2021, aged 71-74y), Norway, and Hoorn study (N=686, aged 50-87y), Netherlands, we examined the cross-sectional associations of plasma sulfur-containing compounds (SCC; methionine, S-adenosylmethionine, S-adenosylhomocysteine, homocysteine, cystathionine, total cysteine (tCys), glutathione and cysteinylglycine) with SCD-16 index (16:1n-7/16:0), estimated from fatty acid profiles of total plasma or serum lipids. Only tCys was consistently associated with SCD-16 index after adjustments for sex and age (HUSK: partial r=0.14; Hoorn: partial r=0.11, P<0.001 for both), and after further adjustments for other SCC, body fat, diet, exercise and plasma lipids (HUSK: partial r=0.07, P=0.004; Hoorn: partial r=0.12, P=0.013). Together with animal data showing an effect of dietary cysteine on SCD1, our results suggest a role for cysteine in SCD1 regulation in humans.

Associations of serum n-3 and n-6 polyunsaturated fatty acids with echocardiographic measures among older adults: the Hoorn Study.

BACKGROUND/OBJECTIVES: Lower circulating polyunsaturated fatty acids (PUFAs) may induce loss of heart function. We investigated whether lower concentrations of n-3 and n-6 PUFAs were associated with less favourable echocardiographic measures and higher heart rate in older Caucasians, cross-sectionally and after 7 years of follow-up. SUBJECTS/METHODS: We used data from the Hoorn Study, a population-based cohort. Cross-sectional data were available for 621 participants and longitudinal data for 336 participants. Mean age was 68.6±6.8 years at baseline. We performed linear regression analyses using n-3 and n-6 PUFAs quartiles-assayed by gas liquid chromatography-with left ventricular ejection fraction (LVEF), left ventricular mass index, left atrial volume index and heart rate. RESULTS: In multivariable analyses (regression coefficient (95% confidence interval)), the lowest eicosapentaenoic acid and docosahexaenoic acid quartiles compared with the highest quartiles were cross-sectionally associated with lower LVEF. Lower eicosapentaenoic acid and docosahexaenoic acid concentrations were associated with higher heart rate: 3.7 b.p.m. (1.5, 6.0; P for trend <0.001) and 3.4 b.p.m. (1.2, 5.6; P for trend 0.001), respectively. Multivariate longitudinal analyses showed a significant trend across quartiles for alpha-linolenic acid in relation to LVEF. The lowest linoleic acid quartile was significantly associated with a decreased LVEF of -4.0% compared with the highest quartile. CONCLUSIONS: This study found no strong evidence of longitudinal associations of eicosapentaenoic acid and docosahexaenoic acid with echocardiographic measures, however, lower concentrations of alpha-linolenic acid and linoleic acid were associated with decreased LVEF. These results provide evidence for a potential protective role of alpha-linolenic acid and linoleic acid in relation to systolic function.

A clinical study of the cognitive effects of benzodiazepines in psychogeriatric patients.

Previous studies have shown cognitive impairment in long-term benzodiazepine users compared to non-users. However, little is known about such effects in a population of geriatric psychiatry patients. The aim of this study was to identify differences between benzodiazepine users and non-users on standardized tests of the cognitive fields of learning and memory, executive functions and vigilance, at admittance to a department of geriatric psychiatry.Hopkins verbal learning test, Stroop test and digit vigilance test were performed in all patients. Test performances were compared between benzodiazepine users (n=168) and non-users (n=73). A multiple linear regression model was used, adjusting for different baseline characteristics (years of education, dementia and depression).No significant differences in test results were found between benzodiazepine users and non-users on 11 out of 12 cognitive tests results. On one of the 12 test results (time used on the digit vigilance test), benzodiazepine users showed better performance compared to non-users (ß=-0.20, p=0.032). This finding was not statistically significant after Bonferroni correction for multiple testing.This study of geriatric psychiatry benzodiazepine users did not reveal cognitive impairment compared to non-users on the cognitive areas tested. Other possible negative consequences of benzodiazepine use should, however, also be considered when prescribing drugs to older patients.

Clinical and biochemical validation of two endophenotypes of schizophrenia defined by levels of polyunsaturated fatty acids in red blood cells.

BACKGROUND: Polyunsaturated fatty acids (PUFAs) are bimodally distributed in acute schizophrenia, suggesting two endophenotypes. We intended to characterize these endophenotypes clinically. Our a priori hypothesis was that low PUFA patients have more negative symptoms. PATIENTS AND METHODS: Patients (aged 18-39) with schizophrenia, schizoaffective or schizophreniform disorders were recruited at hospital admission during an acute episode. The baseline Positive and Negative Syndrome Scale, vital signs and biochemical variables were measured in 97 patients with available RBC PUFA levels. Adjustment for multiple testing was not performed. RESULTS: The median Negative Subscale score was higher (p=0.04) in the low PUFA (25 points, n=30) than in the high PUFA group (19 points, n=67). Among 95 patients with measurements of serum triglycerides, hypertriglyceridaemia was more prevalent (p=0.009) among low PUFA patients (66%) than high PUFA patients (36%). PUFA modified the effect of antipsychotics on triglycerides (p=0.046). Serum glucose and mean corpuscular haemoglobin were higher (p=0.03, 0.001, respectively) in low PUFA than in high PUFA patients. Low PUFA men were heavier (p=0.04) than high PUFA men. CONCLUSIONS: During an acute episode of schizophrenia, patients with low RBC PUFA have more negative symptoms and more metabolic and haematological abnormalities than those with high PUFA. This indicates that PUFA levels define two clinically distinct endophenotypes of the disorder.

The association of fasting plasma sulfur-containing compounds with BMI, serum lipids and apolipoproteins.

BACKGROUND AND AIM: Sulfur amino acids are recognized as potent modulators of lipid metabolism. Plasma total cysteine (tCys) is associated with fat mass, obesity and serum LDL-cholesterol and apolipoprotein (Apo)-B in large population studies. It is not known how fasting plasma concentrations of cysteine precursors and products relate to these associations in humans, given that sulfur-containing compounds (SCC) influence rodent weight gain and serum lipids. METHODS AND RESULTS: We investigated the cross-sectional associations of fasting plasma SCC (methionine, total homocysteine, cystathionine, tCys, taurine and total glutathione) with BMI and fasting serum lipids and apolipoproteins in 854 men and women with and without cardiovascular disease (CVD). In multiple linear regression analysis adjusted for age, gender, CVD and other SCC, neither methionine, taurine, nor total glutathione was associated with BMI. Plasma taurine was, however, inversely related to HDL-cholesterol (partial r = -0.12, p = 0.004) and its associated apoA1 (partial r = -0.18, p < 0.001). Plasma cystathionine correlated positively with triglycerides and BMI, while tCys positively correlated with total cholesterol, LDL-cholesterol (partial r = 0.20, p < 0.001) and its associated apoB. The associations of SCC with serum lipids were independent of BMI. tCys was also independently associated with BMI (partial r = 0.20, p < 0.001) after adjustment for other SCC, glucose, lipids and apolipoproteins. CONCLUSIONS: Fasting tCys is associated with BMI independently of metabolically related SCC. Elevation of plasma SCC is generally associated with an unfavorable lipid profile. The negative relations of plasma taurine with HDL-C and apoA1 deserve further investigation.

Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials.

OBJECTIVES: In the Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial, patients were randomly assigned to homocysteine-lowering B-vitamins or no such treatment. We investigated their effects on cardiovascular outcomes in the trial populations combined, during the trials and during an extended follow-up, and performed exploratory analyses to determine the usefulness of homocysteine as a predictor of cardiovascular outcomes. DESIGN: Pooling of data from two randomized controlled trials (1998-2005) with extended post-trial observational follow-up until 1 January 2008. SETTING: Thirty-six hospitals in Norway. SUBJECTS: 6837 patients with ischaemic heart disease. INTERVENTIONS: One capsule per day containing folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg), or folic acid plus vitamin B12, or vitamin B6 alone or placebo. MAIN OUTCOME MEASURES: Major adverse cardiovascular events (MACEs; cardiovascular death, acute myocardial infarction or stroke) during the trials and cardiovascular mortality during the extended follow-up. RESULTS: Folic acid plus vitamin B12 treatment lowered homocysteine levels by 25% but did not influence MACE incidence (hazard ratio, 1.07; 95% CI, 0.95-1.21) during 39 months of follow-up, or cardiovascular mortality (hazard ratio, 1.12; 95% CI, 0.95-1.31) during 78 months of follow-up, when compared to no such treatment. Baseline homocysteine level was not independently associated with study outcomes. However, homocysteine concentration measured after 1-2 months of folic acid plus vitamin B12 treatment was a strong predictor of MACEs. CONCLUSION: We found no short- or long-term benefit of folic acid plus vitamin B12 on cardiovascular outcomes in patients with ischaemic heart disease. Our data suggest that cardiovascular risk prediction by plasma total homocysteine concentration may be confined to the homocysteine fraction that does not respond to B-vitamins.

Serum concentrations of citalopram--dose-dependent variation in R- and S-enantiomer ratios.

INTRODUCTION: The antidepressive effect of racemic citalopram (CIT) is exerted by S-CIT, while R-CIT is a partial antagonist to S-CIT. Since R-and S-CIT are metabolized by different pathways, we investigated whether the ratio of S- and R-CIT may differ between individuals on the same dose of racemic CIT, and if a possible variability in the R/S-ratio could be dose-dependent. METHODS: A chiral analysis of R- and S-CIT in serum samples taken from 88 female patients receiving treatment with racemic CIT was performed using high-pressure liquid chromatography. RESULTS: The mean levels of R-CIT were significantly higher than those of S-CIT in all dose groups. The R/S-CIT ratio increased from 1.99 to 2.45 with an increase in the dose (p<0.05), and the interindividual variance in the R/S-CIT ratio was up to four-fold on the same dosage. DISCUSSION: Our findings show that the stereoselective metabolism of citalopram IN VIVO has pharmacokinetic consequences reflected by dose dependent variations of enantiomeric drug concentrations, as well as substantial interindividual variabilities in the ratios of the concentrations. The clinical consequences, however, are unclear and should be further explored.

Effect of physiological doses of oral vitamin B12 on plasma homocysteine: a randomized, placebo-controlled, double-blind trial in India.

BACKGROUND/OBJECTIVES: Vitamin B(12) (B(12)) deficiency is common in Indians and a major contributor to hyperhomocysteinemia, which may influence fetal growth, risk of type II diabetes and cardiovascular disease. The purpose of this paper was to study the effect of physiological doses of B(12) and folic acid on plasma total homocysteine (tHcy) concentration. SUBJECTS/METHODS: A cluster randomized, placebo-controlled, double-blind, 2 x 3 factorial trial, using the family as the randomization unit. B(12) was given as 2 or 10 microg capsules, with or without 200 microg folic acid, forming six groups (B(0)F(0), B(2)F(0), B(10)F(0), B(0)F(200), B(2)F(200) and B(10)F(200)). Plasma tHcy concentration was measured before and after 4 and 12 months of supplementation. RESULTS: From 119 families in the Pune Maternal Nutrition Study, 300 individuals were randomized. There was no interaction between B(12) and folic acid (P=0.14) in relation to tHcy concentration change and their effects were analyzed separately: B(0) vs. B(2) vs. B(10); and F(0) vs. F(200). At 12 months, tHcy concentration reduced by a mean 5.9 (95% CI: -7.8, -4.1) micromol/l in B(2), and by 7.1 (95% CI: -8.9, -5.4) micromol/l in B(10), compared to nonsignificant rise of 1.2 (95% CI: -0.5, 2.9) micromol/l in B(0). B(2) and B(10) did not differ significantly. In F(200), tHcy concentration decreased by 4.8 (95% CI: -6.3, -3.3) micromol/l compared to 2.8 (95% CI: -4.3, -1.2) micromol/l in F(0). CONCLUSION: Daily oral supplementation with physiological doses of B(12) is an effective community intervention to reduce tHcy. Folic acid (200 microg per day) showed no additional benefit, neither had any unfavorable effects.

Identification of a novel CYP2C19-mediated metabolic pathway of S-citalopram in vitro.

Systemic exposure of the antidepressant S-citalopram (escitalopram, SCIT) differs several-fold according to variable cytochrome P450 2C19 activity, demonstrating the importance of this enzyme for the metabolic clearance of SCIT in vivo. However, previous studies have indicated that the involvement of CYP2C19 in formation of the metabolite N-desmethyl S-citalopram (SDCIT) is limited. Therefore, the purpose of the present in vitro study was to investigate to what extent the CYP2C19-mediated clearance of SCIT was due to a metabolic pathway different from N-desmethylation and to identify the product(s) of this possible alternative metabolic reaction. CYP2C19-mediated metabolism of SCIT was investigated using recombinant Supersomes expressing human CYP2C19. Initial experiments showed that approximately half of the CYP2C19-mediated clearance of SCIT was accounted for by the N-desmethylation pathway. Subsequent experiments identified that, in addition to SDCIT, the propionic acid metabolite of SCIT (SCIT PROP) was formed by CYP2C19 in vitro. Formation of SCIT PROP accounted for 35% of total CYP2C19-mediated clearance of SCIT (calculated as the ratio between metabolite formation rate and substrate concentration at low substrate concentration). Moreover, analysis of samples from six CYP2C19-genotyped patients treated with SCIT indicated that differences in serum concentrations of SCIT between CYP2C19 genotypes may be due to a combined effect on SCIT PROP and SDCIT formation. Identification of SCIT PROP as a metabolic pathway catalyzed by CYP2C19 might explain why impaired CYP2C19 activity has a substantially larger effect on SCIT exposure than estimated from in vitro data based solely on formation of SDCIT.

Plasma vitamin B12 status and cerebral white-matter lesions.

BACKGROUND AND OBJECTIVE: Elevated homocysteine has been associated with a higher prevalence of cerebral white-matter lesions and infarcts, and worse cognitive performance. This raises the question whether factors involved in homocysteine metabolism, such as vitamin B(12), are also related to these outcomes. This study examined the association of several markers of vitamin B(12) status with cerebral white-matter lesions, infarcts and cognition. METHODS: The study evaluated the association of plasma concentrations of vitamin B(12), methylmalonic acid, holotranscobalamin and transcobalamin saturation with cerebral white-matter lesions and infarcts at baseline and cognition at baseline and during follow-up among 1019 non-demented elderly participants of the population-based Rotterdam Scan Study. Analyses were adjusted for several potential confounders, including homocysteine and folate concentration. RESULTS: Poorer vitamin B(12) status was significantly associated with greater severity of white-matter lesions, in particular periventricular white-matter lesions, in a concentration-related manner. Adjustment for common vascular risk factors (including blood pressure, smoking, diabetes and intima media thickness) did not alter the associations. Adjustment for homocysteine and folate modestly weakened the associations. No association was observed for any of the studied markers of vitamin B(12) status with presence of brain infarcts and baseline cognition or cognitive decline during follow-up. CONCLUSIONS: These results indicate that vitamin B(12) status in the normal range is associated with severity of white-matter lesions, especially periventricular lesions. Given the absence of an association with cerebral infarcts, it is hypothesised that this association is explained by effects on myelin integrity in the brain rather than through vascular mechanisms.

Vitamin B12 status and rate of brain volume loss in community-dwelling elderly.

OBJECTIVES: To investigate the relationship between markers of vitamin B(12) status and brain volume loss per year over a 5-year period in an elderly population. METHODS: A prospective study of 107 community-dwelling volunteers aged 61 to 87 years without cognitive impairment at enrollment. Volunteers were assessed yearly by clinical examination, MRI scans, and cognitive tests. Blood was collected at baseline for measurement of plasma vitamin B(12), transcobalamin (TC), holotranscobalamin (holoTC), methylmalonic acid (MMA), total homocysteine (tHcy), and serum folate. RESULTS: The decrease in brain volume was greater among those with lower vitamin B(12) and holoTC levels and higher plasma tHcy and MMA levels at baseline. Linear regression analysis showed that associations with vitamin B(12) and holoTC remained significant after adjustment for age, sex, creatinine, education, initial brain volume, cognitive test scores, systolic blood pressure, ApoE epsilon4 status, tHcy, and folate. Using the upper (for the vitamins) or lower tertile (for the metabolites) as reference in logistic regression analysis and adjusting for the above covariates, vitamin B(12) in the bottom tertile (<308 pmol/L) was associated with increased rate of brain volume loss (odds ratio 6.17, 95% CI 1.25-30.47). The association was similar for low levels of holoTC (<54 pmol/L) (odds ratio 5.99, 95% CI 1.21-29.81) and for low TC saturation. High levels of MMA or tHcy or low levels of folate were not associated with brain volume loss. CONCLUSION: Low vitamin B(12) status should be further investigated as a modifiable cause of brain atrophy and of likely subsequent cognitive impairment in the elderly.

Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients.

OBJECTIVE: To investigate the impact of CYP2C19 genotype on serum concentrations of sertraline and N-desmethyl sertraline in psychiatric patients. METHODS: Patients treated with sertraline (n = 121) were divided into six subgroups according to CYP2C19 genotype: CYP2C19*17/*17, CYP2C19*1/*17, CYP2C19*1/*1, CYP2C19*17/def, CYP2C19*1/def and CYP2C19def/def (def = allele encoding defective CYP2C19 metabolism, i.e. *2 and *3). Dose-adjusted serum concentrations were compared by linear mixed model analyses using the CYP2C19*1/*1 subgroup as reference. RESULTS: Subgroups carrying one or two alleles encoding defective CYP2C19 metabolism achieved significantly higher mean dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline compared to the CYP2C19*1/*1 subgroup (P < 0.05). The effect of CYP2C19 genotype was expressed as 3.2-fold (sertraline) and 4.5-fold (N-desmethyl sertraline) higher dose-adjusted serum concentrations in the CYP2C19def/def subgroup compared to the CYP2C19*1/*1 subgroup (P < 0.01). The CYP2C19*17 allele had no influence on the dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline. CONCLUSION: The significantly higher serum concentrations associated with alleles encoding defective CYP2C19 metabolism might be of relevance for the clinical outcome of sertraline treatment.