Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain.Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging.Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)–type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals).Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: −0.054 ± 0.004 and −0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: −0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: −0.01; 95% CI: −0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: −0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment.Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.

BACKGROUND Biomarkers and metabolites related to B vitamin function and one-carbon metabolism have been studied as predictors of chronic diseases in studies based on samples stored in biobanks. For most biomarkers, stability data are lacking or fragmentary. METHODS Degradation and accumulation kinetics of 32 biomarkers were determined at 23 °C in serum and plasma (EDTA, heparin, and citrate) collected from 16 individuals and stored for up to 8 days. In frozen serum (−25 °C), stability was studied cross-sectionally in 650 archival samples stored for up to 29 years. Concentration vs time curves were fitted to monoexponential, biexponential, linear, and nonlinear models. RESULTS For many biomarkers, stability was highest in EDTA plasma. Storage effects were similar at room temperature and at −25 °C; notable exceptions were methionine, which could be recovered as methionine sulfoxide, and cystathionine, which decreased in frozen samples. Cobalamin, betaine, dimethylglycine, sarcosine, total homocysteine, total cysteine, tryptophan, asymetric and symmetric dimethyl argenine, creatinine, and methylmalonic acid were essentially stable under all conditions. Most B vitamins (folate and vitamins B2 and B6) were unstable; choline increased markedly, and some amino acids also increased, particularly in serum. The kynurenines showed variable stability. For many biomarkers, degradation (folate and flavin mononucleotide) or accumulation (pyridoxal, riboflavin, choline, amino acids) kinetics at room temperature were non–first order. CONCLUSIONS Data on stability and deterioration kinetics for individual biomarkers are required to optimize procedures for handling serum and plasma, and for addressing preanalytical bias in epidemiological and clinical studies.

We aimed to evaluate 10 biomarkers related to inflammation and the kynurenine pathway, including neopterin, kynurenine:tryptophan ratio, C-reactive protein, tryptophan, and 6 kynurenines, as potential predictors of all-cause and cause-specific mortality in a general population sample. The study cohort was participants involved in a community-based Norwegian study, the Hordaland Health Study (HUSK). We used Cox proportional hazards models to assess associations of the biomarkers with all-cause mortality and competing-risk models for cause-specific mortality. Of the 7,015 participants, 1,496 deaths were recorded after a median follow-up time of 14 years (1998–2012). Plasma levels of inflammatory markers (neopterin, kynurenine:tryptophan ratio, and C-reactive protein), anthranilic acid, and 3-hydroxykynurenine were positively associated with all-cause mortality, and tryptophan and xanthurenic acid were inversely associated. Multivariate-adjusted hazard ratios for the highest (versus lowest) quartiles of the biomarkers were 1.19–1.60 for positive associations and 0.73–0.87 for negative associations. All of the inflammatory markers and most kynurenines, except kynurenic acid and 3-hydroxyanthranilic acid, were associated with cardiovascular disease (CVD) mortality. In this general population, plasma biomarkers of inflammation and kynurenines were associated with risk of all-cause, cancer, and CVD mortality. Associations were stronger for CVD mortality than for mortality due to cancer or other causes.

SummaryCirculating neopterin and kynurenine/tryptophan ratio (KTR) increase during inflammation and serve as markers of cellular immune activation, but data are sparse on other determinants of these markers and metabolites of the kynurenine pathway. We measured neopterin, tryptophan, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid in plasma in two age groups, 45-46 years (n = 3723) and 70-72 years (n = 3329). Differences across categories of the potential determinants, including age, gender, renal function, body mass index (BMI), smoking and physical activity, were tested by Mann-Whitney U-test and multiple linear regression including age group, gender, renal function and lifestyle factors. In this multivariate model, neopterin, KTR and most kynurenines were 20-30% higher in the older group, whereas tryptophan was 7% lower. Men had 6-19% higher concentrations of tryptophan and most kynurenines than women of the same age. Compared to the fourth age-specific estimated glomerular filtration rate (eGFR) quartile, the first quartile was associated with higher concentrations of neopterin (25%) and KTR (24%) and 18-36% higher concentrations of kynurenines, except 3-hydroxyanthranilic acid. Additionally, KTR, tryptophan and all kynurenines, except anthranilic acid, were 2-8% higher in overweight and 3-17% higher in obese, than in normal-weight individuals. Heavy smokers had 4-14% lower levels of tryptophan and most kynurenines than nonsmokers. Age and renal function were the strongest determinants of plasma neopterin, KTR and most kynurenines. These findings are relevant for the design and interpretation of studies investigating the role of plasma neopterin, KTR and kynurenines in chronic diseases.