Helga Refsum

• Olsen, Thomas; Elshorbagy, Amany; Tore, Elena C.; Bastani, Nasser Ezzatkhah; Stolt, Emma Theresia Kjelland & Blokland, Gabriëlla A.M. [Show all 16 contributors for this article] (2026). Higher plasma serine levels are associated with favorable values of metabolic health markers among middle-aged and older adults in The Maastricht Study. GeroScience. ISSN 2509-2715. doi: 10.1007/s11357-026-02237-4. Full text in Research Archive Show summary

  Laboratory studies indicate a mechanistic role for serine in the metabolic benefits induced by dietary restriction of methionine and cysteine. To investigate the association of plasma serine with metabolic health markers in humans, we conducted a cross-sectional analysis of a subset of data from The Maastricht Study (n = 1199). Linear regression analyses (adjusted for confounding variables) were conducted to investigate whether plasma serine is associated with markers of lipid metabolism, glucose homeostasis, and body composition. Interaction analyses were conducted to investigate whether sex, diabetes status, and plasma total cysteine modify the association of serine with metabolic markers. Correlations between dietary intake of sulfur amino acids and plasma amino acids, including methionine and total cysteine, were also investigated. Elevated plasma serine was associated with favorable changes in markers of lipid metabolism (triglycerides, total cholesterol, and indices of multiple fatty acid desaturases), glucose homeostasis (insulin resistance and glucose tolerance), fat utilization (β-hydroxybutyrate, acetoacetate, and acetone), and body composition (visceral and subcutaneous adipose depots, liver fat, and body mass index). Some associations were stronger in males than in females and in individuals with prediabetes and diabetes than in those without diabetes. Associations of plasma serine with body mass index, total fat mass, total lean mass, and subcutaneous adipose tissue weakened as plasma cysteine increased. Combined methionine and cysteine intake was inversely associated with plasma serine. Findings suggest that plasma serine is strongly associated with improved metabolic health in humans. Additional studies are required to confirm whether the associations are causal.

• Kacerova, Tereza; Yates, Abi G.; Dai, Jiayi; Shepherd, Dawn; Pires, Elisabete & Jel, Sebastian de [Show all 16 contributors for this article] (2025). Role of B vitamins in modulating homocysteine and metabolic pathways linked to brain atrophy: Metabolomics insights from the VITACOG trial. Alzheimer's & Dementia. ISSN 1552-5260. 21(7). doi: 10.1002/alz.70521. Full text in Research Archive Show summary

  Abstract INTRODUCTION Elevated total homocysteine (tHcy) is a major predictor of brain atrophy, cognitive decline, and Alzheimer's disease (AD) progression. The VITACOG trial, a randomized, placebo‐controlled study in mild cognitive impairment (MCI), previously showed that B vitamin supplementation lowered tHcy, slowing brain atrophy and cognitive decline; however, the underlying mechanisms remained unclear. METHODS We used untargeted, multi‐platform metabolomics, with nuclear magnetic resonance and liquid chromatography‐mass spectrometry to analyze serum samples from 89 B vitamin–treated and 84 placebo‐treated MCI participants over a 2 year follow‐up period. RESULTS Multivariate modeling distinguished treated from placebo groups with 91.2 ± 1.8% accuracy. B vitamin supplementation induced significant metabolic reprogramming, lowering quinolinic acid, α‐ketoglutarate, α‐ketobutyrate, glucose, and glutamate. DISCUSSION These findings reveal that B vitamins influence metabolic pathways beyond tHcy reduction, particularly the tricarboxylic acid cycle and glutamine–glutamate cycling, critical for brain energy homeostasis and neurotransmission. This metabolic signature supports B vitamin supplementation as a strategy for slowing MCI progression. Highlights Nuclear magnetic resonance and multi‐platform liquid chromatography tandem mass spectrometry metabolomics were performed on serum samples from 89 B vitamin–treated and 84 placebo participants in the VITACOG trial. Multi‐platform metabolomics revealed B vitamin–driven metabolic reprogramming, achieving 91% classification accuracy. B vitamin supplementation modulates key neuroprotective metabolic pathways. Regulation of energy metabolism and neurotransmission by B vitamins contributes to brain health in elderly individuals. B vitamins demonstrate potential as an adjunct therapy in mild cognitive impairment, potentially mitigating progression to Alzheimer's disease.

• Olsen, Thomas; Stolt, Emma Theresia Kjelland; Øvrebø, Bente; Elshorbagy, Amany; Tore, Elena C. & Lee-Ødegård, Sindre [Show all 20 contributors for this article] (2024). Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial. Journal of Translational Medicine. 22(40). doi: 10.1186/s12967-023-04833-w. Full text in Research Archive Show summary

  Background Dietary sulfur amino acid restriction (SAAR) improves metabolic health in animals. In this study, we investigated the effect of dietary SAAR on body weight, body composition, resting metabolic rate, gene expression profiles in white adipose tissue (WAT), and an extensive blood biomarker profile in humans with overweight or obesity. Methods N = 59 participants with overweight or obesity (73% women) were randomized stratified by sex to an 8-week plant-based dietary intervention low (~ 2 g/day, SAAR) or high (~ 5.6 g/day, control group) in sulfur amino acids. The diets were provided in full to the participants, and both investigators and participants were blinded to the intervention. Outcome analyses were performed using linear mixed model regression adjusted for baseline values of the outcome and sex. Results SAAR led to a ~ 20% greater weight loss compared to controls (β 95% CI − 1.14 (− 2.04, − 0.25) kg, p = 0.013). Despite greater weight loss, resting metabolic rate remained similar between groups. Furthermore, SAAR decreased serum leptin, and increased ketone bodies compared to controls. In WAT, 20 genes were upregulated whereas 24 genes were downregulated (FDR < 5%) in the SAAR group compared to controls. Generally applicable gene set enrichment analyses revealed that processes associated with ribosomes were upregulated, whereas processes related to structural components were downregulated. Conclusion Our study shows that SAAR leads to greater weight loss, decreased leptin and increased ketone bodies compared to controls. Further research on SAAR is needed to investigate the therapeutic potential for metabolic conditions in humans. Trial registration: ClinicalTrials.gov identifier: NCT04701346, registered Jan 8th 2021, https://www.clinicaltrials.gov/study/NCT04701346

• Olsen, Thomas; Vinknes, Kathrine Jørgensen; Barvíková, Kristýna; Stolt, Emma Theresia Kjelland; Lee-Ødegård, Sindre & Troensegaard, Hannibal [Show all 18 contributors for this article] (2024). Dietary sulfur amino acid restriction in humans with overweight and obesity: Evidence of an altered plasma and urine sulfurome, and a novel metabolic signature that correlates with loss of fat mass and adipose tissue gene expression. Redox Biology. 73. doi: 10.1016/j.redox.2024.103192. Full text in Research Archive Show summary

  Background In animals, dietary sulfur amino acid restriction (SAAR) improves metabolic health, possibly mediated by altering sulfur amino acid metabolism and enhanced anti-obesogenic processes in adipose tissue. Aim To assess the effects of SAAR over time on the plasma and urine SAA-related metabolites (sulfurome) in humans with overweight and obesity, and explore whether such changes were associated with body weight, body fat and adipose tissue gene expression. Methods Fifty-nine subjects were randomly allocated to SAAR (∼2 g SAA, n = 31) or a control diet (∼5.6 g SAA, n = 28) consisting of plant-based whole-foods and supplemented with capsules to titrate contents of SAA. Sulfurome metabolites in plasma and urine at baseline, 4 and 8 weeks were measured using HPLC and LC-MS/MS. mRNA-sequencing of subcutaneous white adipose tissue (scWAT) was performed to assess changes in gene expression. Data were analyzed with mixed model regression. Principal component analyses (PCA) were performed on the sulfurome data to identify potential signatures characterizing the response to SAAR. Results SAAR led to marked decrease of the main urinary excretion product sulfate (p < 0.001) and plasma and/or 24-h urine concentrations of cystathionine, sulfite, thiosulfate, H2S, hypotaurine and taurine. PCA revealed a distinct metabolic signature related to decreased transsulfuration and H2S catabolism that predicted greater weight loss and android fat mass loss in SAAR vs. controls (all pinteraction < 0.05). This signature correlated positively with scWAT expression of genes in the tricarboxylic acid cycle, electron transport and β-oxidation (FDR = 0.02). Conclusion SAAR leads to distinct alterations of the plasma and urine sulfurome in humans, and predicted increased loss of weight and android fat mass, and adipose tissue lipolytic gene expression in scWAT. Our data suggest that SAA are linked to obesogenic processes and that SAAR may be useful for obesity and related disorders.

• Olsen, Thomas; Refsum, Helga & R., Eiser Arnold (2024). Hyperhomocysteinemia Is Associated With a Myriad of Age-Related Illnesses: A Potential Role for Metal Toxicity. Mayo Clinic proceedings. ISSN 0025-6196. doi: 10.1016/j.mayocp.2024.04.016. Full text in Research Archive
• Holmes, Holly E.; Valentin, Rafael E.; Jernerén, Fredrik; Jager Loots, Celeste A. de; Refsum, Helga & Smith, David [Show all 9 contributors for this article] (2024). Elevated homocysteine is associated with increased rates of epigenetic aging in a population with mild cognitive impairment. Aging Cell. ISSN 1474-9718. 23. doi: 10.1111/acel.14255. Full text in Research Archive Show summary

  Elevated plasma total homocysteine (tHcy) is associated with the development of Alzheimer's disease and other forms of dementia. In this study, we report the relationship between tHcy and epigenetic age in older adults with mild cognitive impairment from the VITACOG study. Epigenetic age and rate of aging (ROA) were assessed using various epigenetic clocks, including those developed by Horvath and Hannum, DNAmPhenoAge, and with a focus on Index, a new principal component-based epigenetic clock that, like DNAmPhenoAge, is trained to predict an individual's “PhenoAge.” We identified significant associations between tHcy levels and ROA, suggesting that hyperhomocysteinemic individuals were aging at a faster rate. Moreover, Index revealed a normalization of accelerated epigenetic aging in these individuals following treatment with tHcy-lowering B-vitamins. Our results indicate that elevated tHcy is a risk factor for accelerated epigenetic aging, and this can be ameliorated with B-vitamins. These findings have broad relevance for the sizable proportion of the worldwide population with elevated tHcy.

• Iversen, Per Ole; Guéant, Jean-Louis; Oussalah, A; Refsum, Helga; Nexo, Ebba & Tjønnfjord, Geir Erland [Show all 7 contributors for this article] (2024). Heterozygous Mutations in Both the AMN and CBS Genes: Double Haploinsufficiency as an Unusual Cause of Vitamin B12 Deficiency-A Case Report. Clinical Case Reports. 12(11). doi: 10.1002/ccr3.9600. Full text in Research Archive Show summary

  Vitamin B12 deficiency is usually simple to diagnose. However, our patient demonstrates that in difficult cases, the ordinary clinician may need a transdisciplinary approach. The finding of a double haploinsufficiency as a possible cause of vitamin B12 deficiency in our patient, illustrates the usefulness of performing large panel clinical exome sequencing.

• Olsen, Thomas; Elshorbagy, Amany; Stolt, Emma Theresia Kjelland; Åsberg, Anders; Zare, Hasse Khiabani & Bastani, Nasser Ezzatkhah [Show all 9 contributors for this article] (2024). Acute effects of oral mesna administration on the full amino acid profile and 3-methylhistidine: secondary results from the CYLOB dose-finding study. Amino Acids. ISSN 0939-4451. 56. doi: 10.1007/s00726-024-03398-2. Full text in Research Archive Show summary

  Plasma total cysteine (tCys) is strongly associated with fat mass in humans. Mesna lowers plasma tCys in a dose-dependent manner, but it is not known whether it interferes with metabolism of other amino acids or protein. In this Phase-1 study, we show that a single dose of mesna administered at 400, 800, 1200 or 1600 mg to 6–7 individuals per dose only slightly affects amino acid profiles, with increases in plasma valine across dose levels. There were no effects of mesna on 3-methylhistidine, a marker of protein breakdown.

• Tore, Elena C.; Adriaans, Bregje C.; Olsen, Thomas; Vinknes, Kathrine Jørgensen; Kooi, M. Eline & Elshorbagy, Amany [Show all 15 contributors for this article] (2024). Estimated stearoyl-CoA desaturase activity mediates the associations of total cysteine with adiposity: The Maastricht Study. Journal of Clinical Lipidology. ISSN 1933-2874. 19(2), p. 348–357. doi: 10.1016/j.jacl.2024.11.005. Full text in Research Archive Show summary

  Background Plasma sulfur amino acids (SAAs), particularly cysteine, are associated with obesity. One proposed mechanism is the altered regulation of the stearoyl-CoA desaturase (SCD) enzyme. Changes in the SCD enzyme activity have been linked to obesity, as well as to plasma SAA concentrations. Objective This study aimed to investigate whether estimated SCD activity mediates the associations between plasma SAAs and measures of overall adiposity and specific fat depots. Methods We examined cross-sectional data from a subset of the Maastricht Study (n=1129, 50.7% men, 56.7% with (pre)diabetes). Concentrations of methionine, total homocysteine, cystathionine, total cysteine (tCys), total glutathione (tGSH) and taurine were measured in fasting plasma. Outcomes included measures of overall, peripheral and central adiposity, and liver fat. SCD activity was estimated by ratios of serum fatty acids as SCD16 and SCD18 indices. The associations between plasma SAAs and measures of adiposity or liver fat were examined with multiple linear regression analysis. Multiple mediation analysis was used to investigate whether the significant associations were mediated by SCD16 and SCD18 indices. Results Plasma tCys was positively associated with all adiposity measures (β ranged from 0.15 to 0.30). SCD16 significantly mediated all associations (proportion mediated ranged from 5.1% to 9.7%). Inconsistent mediation effects were found for SCD18. Despite a significant inverse association of plasma tGSH with all adiposity measures (β ranged from -0.08 to -0.16), no significant mediation effect was found. Conclusions Plasma tCys may promote excessive body fat accumulation via upregulation of SCD activity.

• Turner, Cheryl; Refsum, Helga & Bastani, Nasser Ezzatkhah (2023). Determination of underivatized amino acids in human plasma using ion pair liquid chromatography/tandem mass spectrometry. Journal of chromatography. B. ISSN 1570-0232. 1229, p. 1–9. doi: 10.1016/j.jchromb.2023.123893. Full text in Research Archive Show summary

  Accurate quantification of amino acids (AA) is essential for several applications, including clinical research, food analysis, and pharmaceutical studies. In this study, we developed an analytical method based on liquid chromatography with electrospray ionization coupled to tandem mass spectrometry detection (LC-ESI-MS/MS). This method was devised to accurately quantify a spectrum of amino acids, notably taurine, creatinine, glutathione (GSH), and sulfur-containing amino acids (SAAs) such as methionine, cysteine, and homocysteine, using only 10 μL of human plasma. A stable isotope derivative of each AA is used as an internal standard (IS) for accurate quantification. For retention and separation on a C18 column, heptafluorobutyric acid (HFBA) was employed as an ion pair agent. Multiple reaction monitoring (MRM) in positive mode with the precursor-to-product ion transitions at m/z is used for quantification. The method showed excellent linearity for all AA with a high correlation coefficient (r > 0.9927). The linear fit indicates that the detector response is linear over the tested range of standard concentrations. The accuracy and precision of the method were within the acceptable range of 92–110% and < 15%, respectively. The limit of detection (LOD) and limit of quantification (LOQ) were in the range of 0.001–1.80 µM and 0.004–6.0 µM, respectively. No significant ion suppression or carry over was observed. In conclusion, the assay was validated and found to have adequate accuracy, precision, linearity, sensitivity and selectivity. The assay has been successfully applied to the analysis of human plasma.

• Fung, Erik; Ng, Kwan Hung; Kwok, Timothy; Lui, Leong-Ting; Palaniswamy, Saranya & Chan, Queenie [Show all 17 contributors for this article] (2023). Divergent Survival Outcomes Associated with Elevated Branched-Chain Amino Acid Levels among Older Adults with or without Hypertension and Diabetes: A Validated, Prospective, Longitudinal Follow-Up Study. Biomolecules. 13(8). doi: 10.3390/biom13081252. Full text in Research Archive Show summary

  Branched-chain amino acids are critical metabolic intermediates that can indicate increased risk of cardiometabolic disease when levels are elevated or, alternatively, suggest sufficient mitochondrial energy metabolism and reserve in old age. The interpretation of BCAA levels can be context-dependent, and it remains unclear whether abnormal levels can inform prognosis. This prospective longitudinal study aimed to determine the interrelationship between mortality hazard and fasting serum BCAA levels among older men and women aged ≥65 years with or without hypertension and diabetes mellitus. At baseline (0Y), fasting serum BCAA concentration in 2997 community-living older men and women were measured. Approximately 14 years later (14Y), 860 study participants returned for repeat measurements. Deaths were analysed and classified into cardiovascular and non-cardiovascular causes using International Classification of Diseases codes. Survival analysis and multivariable Cox regression were performed. During a median follow-up of 17Y, 971 (78.6%) non-cardiovascular and 263 (21.4%) cardiovascular deaths occurred among 1235 (41.2%) deceased (median age, 85.8 years [IQR 81.7–89.7]). From 0Y to 14Y, BCAA levels declined in both sexes, whereas serum creatinine concentration increased (both p &lt; 0.0001). In older adults without hypertension or diabetes mellitus, the relationship between mortality hazard and BCAA level was linear and above-median BCAA levels were associated with improved survival, whereas in the presence of cardiometabolic disease the relationship was U-shaped. Overall, adjusted Cox regression determined that each 10% increment in BCAA concentration was associated with a 7% (p = 0.0002) and 16% (p = 0.0057) reduction in mortality hazard estimated at 0Y and 14Y, respectively. Our findings suggested that abnormally high or low (dyshomeostatic) BCAA levels among older adults with hypertension and/or diabetes mellitus were associated with increased mortality, whereas in those with neither disease, increased BCAA levels was associated with improved survival, particularly in the oldest-old.

• Tore, Elena C.; Eussen, Simone; Bastani, Nasser Ezzatkhah; Dagnelie, Pieter; Elshorbagy, Amany K & Grootswagers, Pol [Show all 14 contributors for this article] (2023). The Associations of Habitual Intake of Sulfur Amino Acids, Proteins and Diet Quality with Plasma Sulfur Amino Acid Concentrations: The Maastricht Study. Journal of Nutrition. ISSN 0022-3166. 153(7), p. 2027–2040. doi: 10.1016/j.tjnut.2023.05.008. Full text in Research Archive
• Grande, Giulia; Hooshmand, Babak; Vetrano, Davide Liborio; Smith, David A; Refsum, Helga & Fratiglioni, Laura [Show all 12 contributors for this article] (2023). Association of Long-term Exposure to Air Pollution and Dementia Risk: The Role of Homocysteine, Methionine, and Cardiovascular Burden. Neurology. ISSN 0028-3878. 101(12), p. E1231–E1240. doi: 10.1212/WNL.0000000000207656. Full text in Research Archive Show summary

  Background and Objectives Growing evidence links air pollution with dementia risk, but the biological mechanisms are largely unknown. We investigated the role played by homocysteine (tHcy) and methionine in this association and explored whether this could be explained by cardiovascular diseases (CVDs). Methods Data were extracted from the ongoing Swedish National study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study. At baseline, 2,512 dementia-free participants were examined up to 2013 (mean follow-up: 5.18 ± 2.96 years). Two air pollutants (particulate matter ≤2.5 μm [PM2.5] and nitrogen oxides [NOx]) were assessed yearly from 1990 until 2013 using dispersion models at residential addresses. The hazard ratio of dementia over air pollution levels was estimated using Cox models adjusted for age, sex, education, smoking, socioeconomic status, physical activity, retirement age, creatinine, year of assessment, and the use of supplements. The total effect of air pollutants on dementia was decomposed into 4 pathways involving tHcy/methionine: (1) direct effect; (2) indirect effect (mediation); (3) effect due to interaction; and (4) effect due to both mediation and interaction. To test whether the association was independent from CVDs (ischemic heart disease, atrial fibrillation, heart failure, and stroke), we repeated the analyses excluding those individuals who developed CVDs. Results The mean age of the study participants was 73.4 years (SD: 10.4), and 62.1% were female individuals. During an average period of 5 years (mean: 5.18; SD: 2.96 years), 376 cases with incident dementia were identified. There was a 70% increased hazard of dementia per unit increase of PM2.5 during the 5 years before baseline (hazard ratio [HR]: 1.71; 95% CI 1.33–2.09). Overall, 50% (51.6%; 95% CI 9.0–94.1) of the total effect of PM2.5 on dementia was due to mediation of tHcy (6.6%; 95% CI 1.6–11.6) and/or interaction (47.8%; 95% CI 4.9–91.7) with tHcy and 48.4% (p = 0.03) to the direct effect of PM2.5 on dementia. High levels of methionine reduced the dementia hazard linked to PM2.5 by 31% (HR: 0.69; 95% CI 0.56–0.85) with 24.8% attributable to the interaction with methionine and 25.9% (p = 0.001) to the direct effect of PM2.5. No mediation effect was found through methionine. Attenuated results were obtained for NOx. Findings for tHcy were attenuated after excluding those who developed CVDs, while remained similar for methionine. Discussion High levels of homocysteine enhanced the dementia risk attributed to air pollution, while high methionine concentrations reduced this risk. The impact of homocysteine on cardiovascular conditions partly explains this association. Alternative pathways other than cardiovascular mechanisms may be at play between methionine and dementia.

• Vinknes, Kathrine Jørgensen; Olsen, Thomas; Zare, Hasse Khiabani; Bastani, Nasser Ezzatkhah; Stolt, Emma Theresia Kjelland & Dahl, Anja Falkenhaug [Show all 11 contributors for this article] (2023). Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I, dose-finding study. Diabetes, obesity and metabolism. ISSN 1462-8902. 25(11), p. 3161–3170. doi: 10.1111/dom.15210. Full text in Research Archive Show summary

  Abstract Aim To investigate whether mesna—sodium‐2‐mercaptoethane sulfonate) can reduce diet‐induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. Methods C3H/HeH mice were shifted to a high‐fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24‐hour urine. Results Compared with controls, mesna‐treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; P overall  = .002), but similar lean mass gain. In men with overweight, mesna doses of 400‐1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post‐dosing). With increasing mesna dose, tCys AUC 0‐12h decreased ( P trend  &lt; .001), and urine tCys excretion increased ( P trend  = .004). Conclusions Mesna reduces diet‐induced fat gain in mice. In men with overweight, single oral doses of mesna (800‐1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys‐lowering by repeated mesna administration on weight loss in humans deserves investigation.

• Su, Yi; Elshorbagy, Amany; Turner, Cheryl; Refsum, Helga & Kwok, Timothy (2022). The Association of Circulating Amino Acids and Dietary Inflammatory Potential with Muscle Health in Chinese Community-Dwelling Older People. Nutrients. 14(12). doi: 10.3390/nu14122471. Full text in Research Archive Show summary

  Amino acids (AAs) and dietary inflammatory potential play essential roles in muscle health. We examined the associations of dietary inflammatory index (DII) of habitual diet with serum AA profile, and ascertained if the associations between DII and muscle outcomes were mediated by serum AAs, in 2994 older Chinese community-dwelling men and women (mean age 72 years) in Hong Kong. Higher serum branched chain AAs (BCAAs), aromatic AAs and total glutathione (tGSH) were generally associated with better muscle status at baseline. A more pro-inflammatory diet, correlating with higher serum total homocysteine and cystathionine, was directly (90.2%) and indirectly (9.8%) through lower tGSH associated with 4-year decline in hand grip strength in men. Higher tGSH was associated with favorable 4-year changes in hand grip strength, gait speed and time needed for 5-time chair stands in men and 4-year change in muscle mass in women. Higher leucine and isoleucine were associated with decreased risk of sarcopenia in men; the associations were abolished after adjustment for BMI. In older men, perturbations in serum sulfur AAs metabolism may be biomarkers of DII related adverse muscle status, while the lower risk of sarcopenia with higher BCAAs may partly be due to preserved BMI.

• Tore, Elena C.; Elshorbagy, Amany K.; Bakers, Frans CH; Brouwers, Marin C.G.J.; Dagnelie, Pieter & Eussen, Simone J. [Show all 17 contributors for this article] (2022). Associations between plasma sulfur amino acids and specific fat depots in two independent cohorts: CODAM and The Maastricht Study. European Journal of Nutrition. ISSN 1436-6207. doi: 10.1007/s00394-022-03041-4. Full text in Research Archive Show summary

  Abstract Purpose Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. Methods We examined cross-sectional subsets from the CODAM cohort ( n  = 470, 61.3% men, median [IQR]: 67 [61, 71] years) and The Maastricht Study (DMS; n  = 371, 53.4% men, 63 [55, 68] years), enriched with (pre)diabetic individuals. SAAs were measured in fasting EDTA plasma with LC–MS/MS. Outcomes comprised BMI, skinfolds, waist circumference (WC), dual-energy X-ray absorptiometry (DXA, DMS), body composition, abdominal subcutaneous and visceral adipose tissues (CODAM: ultrasound, DMS: MRI) and liver fat (estimated, in CODAM, or MRI-derived, in DMS, liver fat percentage and fatty liver disease). Associations were examined with linear or logistic regressions adjusted for relevant confounders with z-standardized primary exposures and outcomes. Results Methionine was associated with all measures of liver fat, e.g ., fatty liver disease [CODAM: OR = 1.49 (95% CI 1.19, 1.88); DMS: OR = 1.51 (1.09, 2.14)], but not with other fat depots. tCys was associated with overall obesity, e.g., BMI [CODAM: β  = 0.19 (0.09, 0.28); DMS: β  = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: β  = 0.15 (0.08, 0.23); DMS: β  = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: β  = 0.16 (0.08, 0.25); DMS: β  = 0.17 (0.08, 0.27)]. Associations of tCys with VAT and liver fat were inconsistent. Other SAAs were not associated with body fat. Conclusion Plasma concentrations of methionine and tCys showed distinct associations with different fat depots, with similar strengths in the two cohorts.

• Wu, Yuanyuan; Smith, A. David; Bastani, Nasser Ezzatkhah; Refsum, Helga & Kwok, Timothy (2022). The dihydrofolate reductase 19-bp deletion modifies the beneficial effect of B-vitamin therapy in mild cognitive impairment: Pooled study of two randomized placebo-controlled trials. Human Molecular Genetics. ISSN 0964-6906. 31(7), p. 1151–1158. doi: 10.1093/hmg/ddab246. Full text in Research Archive Show summary

  Abstract Background: Higher serum homocysteine is associated with cognitive decline in older people. But homocysteine-lowering trials including folic acid (FA) show inconsistent results on cognitive decline. The reduction of FA to dihydrofolate by dihydrofolate reductase (DHFR) is slow in humans. Objective: We examined the effects of the DHFR 19-bp deletion/insertion (del/ins) polymorphism on FA-containing treatment on cognitive decline and brain atrophy in older people with mild cognitive impairment (MCI). Methods: This study used pooled data from two randomized B-vitamin trials on 545 MCI subjects who received either FA-containing B vitamins or placebo for 24 months. Subjects were typed for the DHFR genotype. Primary outcome was the Clinical Dementia Rating scale-global score (CDR-global). Secondary outcomes were CDR-sum of boxes score (CDR-SOB), memory and executive Z-scores and whole brain atrophy rate by serial MRI. Results: The proportions of subjects with del/del, del/ins and ins/ins genotype were 29.5, 44.3 and 26.1%, respectively. DHFR genotypes modified the effects of B vitamins on CDR-global, CDR-SOB and executive function Z-score (Pinteraction = 0.017, 0.014 and 0.052, respectively), with significant benefits being observed only in those with ins/ins genotype (Beta = −1.367, −0.614 and 0.315, P = 0.004, 0.014 and 0.012, respectively). The interaction was not significant for memory Z-score and whole brain atrophy rate. Notably, the supplements only slowed brain atrophy in members of the ‘ins/ins’ group who were not using aspirin. Conclusions: Our data indicate that the beneficial effects of B vitamins including FA on cognitive function are only apparent in those with ins/ins genotype, i.e. relatively better preserved DHFR activity.

• Nichenametla, Sailendra N.; Mattocks, Dwight A.L.; Cooke, Diana; Midya, Vishal; Malloy, Virginia L. & Mansilla, Wilfredo [Show all 18 contributors for this article] (2022). Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism. Aging Cell. ISSN 1474-9718. 21(12). doi: 10.1111/acel.13739. Full text in Research Archive Show summary

  Decreasing the dietary intake of methionine exerts robust anti-adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), that is, sulfur amino acid restriction (SAAR). Contrarily, SAAR diets formulated for human consumption included cysteine, and thus might have exerted only MR. Epidemiological studies positively correlate body adiposity with plasma cysteine but not methionine, suggesting that CR, but not MR, is responsible for the anti-adiposity effects of SAAR. Whether this is true, and, if so, the underlying mechanisms are unknown. Using methionine- and cysteine-titrated diets, we demonstrate that the anti-adiposity effects of SAAR are due to CR. Data indicate that CR increases serinogenesis (serine biosynthesis from non-glucose substrates) by diverting substrates from glyceroneogenesis, which is essential for fatty acid reesterification and triglyceride synthesis. Molecular data suggest that CR depletes hepatic glutathione and induces Nrf2 and its downstream targets Phgdh (the serine biosynthetic enzyme) and Pepck-M. In mice, the magnitude of SAAR-induced changes in molecular markers depended on dietary fat concentration (60% fat >10% fat), sex (males > females), and age-at-onset (young > adult). Our findings are translationally relevant as we found negative and positive correlations of plasma serine and cysteine, respectively, with triglycerides and metabolic syndrome criteria in a cross-sectional epidemiological study. Controlled feeding of low-SAA, high-polyunsaturated fatty acid diets increased plasma serine in humans. Serinogenesis might be a target for treating hypertriglyceridemia.

• Elshorbagy, Amany K.; Turner, Cheryl; Bastani, Nasser Ezzatkhah; Refsum, Helga & Kwok, Timothy (2022). The association of serum sulfur amino acids and related metabolites with incident diabetes: a prospective cohort study. European Journal of Nutrition. ISSN 1436-6207. 61, p. 3161–3173. doi: 10.1007/s00394-022-02872-5. Full text in Research Archive
• Elshorbagy, Amany; Bastani, Nasser Ezzatkhah; Lee-Ødegård, Sindre; Øvrebø, Bente; Yasein, Nadia Haj & Svendsen, Karianne [Show all 10 contributors for this article] (2022). The association of fasting plasma thiol fractions with body fat compartments, biomarker profile, and adipose tissue gene expression. Amino Acids. ISSN 0939-4451. doi: 10.1007/s00726-022-03229-2. Full text in Research Archive Show summary

  Abstract People with high plasma total cysteine (tCys) have higher fat mass and higher concentrations of the atherogenic apolipoprotein B (apoB). The disulfide form, cystine, enhanced human adipogenesis and correlated with total fat mass in a Middle-Eastern cohort. In 35 European adults with overweight (88.6% women) and with dual-X-ray absorptiometry measurements of regional fat, we investigated how cystine compared to other free disulfides in their association with total regional adiposity, plasma lipid and glucose biomarkers, and adipose tissue lipid enzyme mRNA ( n  = 19). Most total plasma homocysteine (tHcy) (78%) was protein-bound; 63% of total glutathione (tGSH) was reduced. tCys was 49% protein-bound, 30% mixed-disulfide, 15% cystine, and 6% reduced. Controlling for age and lean mass, cystine and total free cysteine were the fractions most strongly associated with android and total fat: 1% higher cystine predicted 1.97% higher android fat mass (95% CI 0.64, 3.31) and 1.25% (0.65, 2.98) higher total fat mass (both p  = 0.005). A positive association between tCys and apoB ( β : 0.64%; 95% CI 0.17, 1.12%, p  = 0.009) was apparently driven by free cysteine and cystine; cystine was also inversely associated with the HDL-associated apolipoprotein A1 ( β : −0.57%; 95% CI −0.96, −0.17%, p  = 0.007). No independent positive associations with adiposity were noted for tGSH or tHcy fractions. Plasma cystine correlated with CPT1a mRNA (Spearman’s r  = 0.68, p  = 0.001). In conclusion, plasma cystine—but not homocysteine or glutathione disulfides—is associated with android adiposity and an atherogenic plasma apolipoprotein profile. The role of cystine in human adiposity and cardiometabolic risk deserves investigation. ClinicalTrials.gov identifiers: NCT02647970 and NCT03629392.

• Vinknes, Kathrine; Refsum, Helga; Turner, Cheryl; Khaw, Kay-Tee; Wareham, Nicholas J. & Forouhi, Nita G. [Show all 7 contributors for this article] (2021). Plasma Sulfur Amino Acids and Risk of Cerebrovascular Diseases: A Nested Case-Control Study in the EPIC-Norfolk Cohort. Stroke. ISSN 0039-2499. 52(1), p. 172–180. doi: 10.1161/STROKEAHA.120.029177. Full text in Research Archive
• Alshahawy, Rasha; Habachi, Nihal El; Allam, Eman; Jernerén, Fredrik; Refsum, Helga & Elshorbagy, Amany K (2021). Changes in plasma fatty acids and related biomarkers during transition to an exclusively plant- and fish-based diet in healthy adults. Nutrition - The International Journal of Applied and Basic Nutritional Sciences. ISSN 0899-9007. 90. doi: 10.1016/j.nut.2021.111306. Full text in Research Archive
• Perła-Kaján, Joanna; Włoczkowska, Olga; Zioła-Frankowska, Anetta; Frankowski, Marcin; Smith, A. David & Jager, Celeste de [Show all 8 contributors for this article] (2021). Paraoxonase 1, B Vitamins Supplementation, and Mild Cognitive Impairment. Journal of Alzheimer's Disease. ISSN 1387-2877. 81(3), p. 1211–1229. doi: 10.3233/JAD-210137. Full text in Research Archive Show summary

  Background: Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer’s disease. Objective: We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI). Methods: Individuals with MCI (n = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) (n = 95) or placebo (n = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates. Results: In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N-Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition. Conclusion: PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI.

• Wu, Y.; Smith, A.D.; Refsum, H. & Kwok, Timothy (2021). 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. The Journal of Nutrition, Health & Aging. ISSN 1279-7707. 25, p. 1154–1160. doi: 10.1007/s12603-021-1708-1. Full text in Research Archive Show summary

  Abstract 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.

• Olsen, Thomas; Øvrebø, Bente; Turner, Cheryl; Bastani, Nasser Ezzatkhah; Refsum, Helga & Vinknes, Kathrine (2021). Effects of short-term methionine and cysteine restriction and enrichment with polyunsaturated fatty acids on oral glucose tolerance, plasma amino acids, fatty acids, lactate and pyruvate: results from a pilot study. BMC Research Notes. 14(43). doi: 10.1186/s13104-021-05463-5. Full text in Research Archive Show summary

  Objective In this 7-day pilot study we randomized healthy, normal-weight men and women to either a dietary intervention with methionine and cysteine restriction enriched in PUFA (Met/Cyslow + PUFA, n = 7) or with high contents of methionine, cysteine and SFA (Met/Cyshigh + SFA, n = 7). The objective was to describe the short-term responses in oral glucose tolerance, amino acid profile, total fatty acid profile, pyruvate and lactate following a Met/Cyslow + PUFA diet vs. Met/Cyshigh + SFA. Results The diet groups consisted of five women and two men, aged 20–38 years. After the 7-d intervention median pre- and post-oral glucose tolerance test (OGTT) glucose concentrations were 5 mmol/L and 4 mmol/L respectively in the Met/Cyslow + PUFA group. In the Met/Cyshigh + SFA group, median pre- and post-OGTT glucose concentrations were 4.8 mmol/L and 4.65 mmol/L after the 7-d intervention. The responses in the amino acid profiles were similar in both groups during the intervention with the exception of serine. Fatty acids decreased from baseline to day 7 in both groups. Plasma lactate and pyruvate were similar for both groups with an increase to day 3 before approaching baseline values at day 7. Trial registration ClinicalTrials.gov: NCT02647970, registration date: January 6th 2016.

• Jakubowski, Hieronim; Zioła-Frankowska, Anetta; Frankowski, Marcin; Perła-Kaján, Joanna; Refsum, Helga & Jager, Celeste A. De [Show all 7 contributors for this article] (2021). B Vitamins Prevent Iron-Associated Brain Atrophy and Domain-Specific Effects of Iron, Copper, Aluminum, and Silicon on Cognition in Mild Cognitive Impairment. Journal of Alzheimer's Disease. ISSN 1387-2877. 84(3), p. 1039–1055. doi: 10.3233/JAD-215085. Full text in Research Archive Show summary

  Background: Metals, silicon, and homocysteine are linked to Alzheimer’s disease. B vitamin therapy lowers homocysteine and slows brain atrophy and cognitive decline in mild cognitive impairment (MCI). Objective: Examine metals and silicon as predictors of cognition/brain atrophy in MCI, their interaction with homocysteine and cysteine, and how B vitamins affect these relationships. Methods: MCI participants (n = 266, 77.6-year-old, 60.7% female) in VITACOG trial were randomized to receive daily folic acid (0.8 mg)/vitamin B12 (0.5 mg)/vitamin B6 (20 mg) (n = 133) or placebo for two years. At baseline and end-of-study, cranial MRIs were obtained from 168 participants, cognition was analyzed by neuropsychological tests, and serum iron, copper, arsenic, aluminum, and silicon quantified by inductively-coupled plasma mass spectrometry in 196 participants. Data were analyzed by bivariate and multiple regression. Results: Baseline iron, cysteine, and homocysteine were significantly associated with brain atrophy rate. Homocysteine effects on brain atrophy rate were modified by iron and cysteine. At baseline, iron, copper, aluminum, and silicon were significantly associated with one or more domains of cognition: semantic memory, verbal episodic memory, attention/processing speed, and executive function. At end-of-study, baseline iron, copper, aluminum, and silicon predicted cognition in at least one domain: semantic memory, verbal episodic memory, visuospatial episodic memory, attention/processing speed, and global cognition in the placebo but not the B vitamin group. Conclusion: Disparate effects of serum iron, copper, aluminum, silicon, and homocysteine on cognition and brain atrophy in MCI suggest that cognitive impairment is independent of brain atrophy. These factors showed domain-specific associations with cognition, which were abrogated by B vitamin therapy.

• Włoczkowska, Olga; Perła-Kaján, Joanna; Smith, A. David; Jager, Celeste de; Refsum, Helga & Jakubowski, Hieronim (2021). Anti-N-homocysteine-protein autoantibodies are associated with impaired cognition. Alzheimer's and Dementia: Translational Research and Clinical Interventions. 7(1), p. 1–10. doi: 10.1002/trc2.12159. Full text in Research Archive Show summary

  Introduction Elevated homocysteine (Hcy) and related metabolites accelerate Alzheimer's disease. Hcy-lowering B vitamins slow brain atrophy/cognitive decline in mild cognitive impairment (MCI). Modification with Hcy-thiolactone generates auto-immunogenic N-Hcy-protein. We tested a hypothesis that anti-N-Hcy-protein autoantibodies predict cognition in individuals with MCI participating in a randomized, double-blind, placebo-controlled VITACOG trial of B vitamins. Methods Participants with MCI (n = 196, 76.8 years old, 60% women) were randomly assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg), and B6 (20 mg) (n = 98) or placebo (n = 98) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of patients (n = 167) by magnetic resonance imaging. Anti N-Hcy-protein auto-antibodies were quantified by enzyme-linked immunosorbent assay. Associations among anti-N-Hcy-protein autoantibodies, cognition, and brain atrophy were examined by multiple regression analysis. Results At baseline, anti-N-Hcy-protein autoantibodies were significantly associated with impaired global cognition (Mini-Mental State Examination [MMSE]), episodic memory (Hopkins Verbal Learning Test-revised), and attention/processing speed (Map Search). At the end of the study, anti-N-Hcy-protein autoantibodies were associated with impaired global cognition (MMSE) and attention/processing speed (Trail Making A). In the placebo group, baseline anti-N-Hcy-protein autoantibodies predicted, independently of Hcy, global cognition (Telephone Inventory for Cognitive Status modified [TICS-m]; MMSE) and attention/processing speed (Trail Making A) but not brain atrophy, at the end of study. B-vitamin treatment abrogated association of anti-N-Hcy-protein autoantibodies with cognition. Discussion These findings suggest that anti-N-Hcy-protein autoantibodies can impair functional (attention/processing speed and global cognition), but not structural (brain atrophy), aspects of cognition. Anti-N-Hcy-protein autoantibodies are a new factor associated with impaired cognition, which could be ameliorated by B vitamins.

• Elkafrawy, Hagar; Mehanna, Radwa; Ali, Fayrouz; Barghash, Ayman; Dessouky, Iman & Jernerén, Fredrik [Show all 9 contributors for this article] (2021). Extracellular cystine influences human preadipocyte differentiation and correlates with fat mass in healthy adults. Amino Acids. ISSN 0939-4451. 53, p. 1623–1634. doi: 10.1007/s00726-021-03071-y. Full text in Research Archive Show summary

  Abstract Plasma cysteine is associated with human obesity, but it is unknown whether this is mediated by reduced, disulfide (cystine and mixed-disulfides) or protein-bound (bCys) fractions. We investigated which cysteine fractions are associated with adiposity in vivo and if a relevant fraction influences human adipogenesis in vitro. In the current study, plasma cysteine fractions were correlated with body fat mass in 35 adults. Strong positive correlations with fat mass were observed for cystine and mixed disulfides ( r  ≥ 0.61, P  &lt; 0.001), but not the quantitatively major form, bCys. Primary human preadipocytes were differentiated in media containing cystine concentrations varying from 10–50 μM, a range similar to that in plasma. Increasing extracellular cystine (10–50 μM) enhanced mRNA expression of PPARG2 (to sixfold ) , PPARG1 , PLIN1 , SCD1 and CDO1 ( P  = 0.042– &lt; 0.001). Adipocyte lipid accumulation and lipid-droplet size showed dose-dependent increases from lowest to highest cystine concentrations ( P  &lt; 0.001), and the malonedialdehyde/total antioxidant capacity increased, suggesting increased oxidative stress. In conclusion, increased cystine concentrations, within the physiological range, are positively associated with both fat mass in healthy adults and human adipogenic differentiation in vitro. The potential role of cystine as a modifiable factor regulating human adipocyte turnover and metabolism deserves further study.

• Smith, A. David; Jernerén, Fredrik & Refsum, Helga (2021). ω-3 fatty acids and their interactions. American Journal of Clinical Nutrition. ISSN 0002-9165. 113(4), p. 775–778. doi: 10.1093/ajcn/nqab013. Full text in Research Archive
• Smith, A.D. & Refsum, Helga (2021). Homocysteine – from disease biomarker to disease prevention. Journal of Internal Medicine. ISSN 0954-6820. 290(4), p. 826–854. doi: 10.1111/joim.13279. Full text in Research Archive
• Stolt, Emma Theresia Kjelland; Olsen, Thomas; Elshorbagy, Amany; Kozich, Viktor; Greevenbroek, Marleen M.J. Van & Øvrebø, Bente [Show all 10 contributors for this article] (2021). Sulfur amino acid restriction, energy metabolism and obesity: a study protocol of an 8-week randomized controlled dietary intervention with whole foods and amino acid supplements. Journal of Translational Medicine. 19. doi: 10.1186/s12967-021-02824-3. Full text in Research Archive Show summary

  Background Dietary sulfur amino acid (SAA) restriction is an established animal model for increasing lifespan and improving metabolic health. Data from human studies are limited. In the study outlined in this protocol, we will evaluate if dietary SAA restriction can reduce body weight and improve resting energy expenditure (REE) and parameters related to metabolic health. Method/design Men and women (calculated sample size = 60), aged 18–45 years, with body mass index of 27–35 kg/m2 will be included in a double-blind 8-week dietary intervention study. The participants will be randomized in a 1:1 manner to a diet with either low or high SAA. Both groups will receive an equal base diet consisting of low-SAA plant-based whole foods and an amino acid supplement free of SAA. Contrasting SAA contents will be achieved using capsules with or without methionine and cysteine (SAAhigh, total diet SAA ~ 50–60 mg/kg body weight/day; SAAlow, total diet SAA ~ 15–25 mg/kg body weight/day). The primary outcome is body weight change. Data and material collection will also include body composition (dual X-ray absorptiometry), resting energy expenditure (whole-room indirect calorimetry) and samples of blood, urine, feces and adipose tissue at baseline, at 4 weeks and at study completion. Measures will be taken to promote and monitor diet adherence. Data will be analyzed using linear mixed model regression to account for the repeated measures design and within-subject correlation. Discussion The strength of this study is the randomized double-blind design. A limitation is the restrictive nature of the diet which may lead to poor compliance. If this study reveals a beneficial effect of the SAAlow diet on body composition and metabolic health, it opens up for new strategies for prevention and treatment of overweight, obesity and its associated disorders. Trial registration ClinicalTrials.gov: NCT04701346, Registration date: January 8th, 2021

• Pérez, Laura M.; Hooshmand, Babak; Mangialasche, Francesca; Mecocci, Patrizia; Smith, A David & Refsum, Helga [Show all 10 contributors for this article] (2020). Glutathione Serum Levels and Rate of Multimorbidity Development in Older Adults. The journals of gerontology. Series A, Biological sciences and medical sciences. ISSN 1079-5006. 75(6), p. 1089–1094. doi: 10.1093/gerona/glz101. Full text in Research Archive Show summary

  Abstract We aimed to investigate the association between baseline levels of total serum glutathione (tGSH) and rate of chronic disease accumulation over time. The study population (n = 2,596) was derived from a population-based longitudinal study on ≥60-year-olds living in Stockholm. Participants were clinically assessed at baseline, 3- and 6-year follow-ups. Multimorbidity was measured as the number of chronic conditions from a previously built list of 60 diseases. Linear mixed models were applied to analyze the association between baseline tGSH levels and the rate of multimorbidity development over 6 years. We found that at baseline, participants with ≥4 diseases had lower tGSH levels than participants with no chronic conditions (3.3 vs 3.6 µmol/L; p &amp;lt; .001). At follow-up, baseline levels of tGSH were inversely associated with the rate of multimorbidity development (β * time: −0.044, p &amp;lt; .001) after adjusting for age, sex, education, levels of serum creatinine, C-reactive protein, albumin, body mass index, smoking, and time of dropout or death. In conclusion, serum levels of tGSH are inversely associated with multimorbidity development; the association exists above and beyond the link between tGSH and specific chronic conditions. Our findings support the hypothesis that tGSH is a biomarker of multisystem dysregulation that eventually leads to multimorbidity.

• Olsen, Thomas; Turner, Cheryl; Øvrebø, Bente; Bastani, Nasser Ezzatkhah; Refsum, Helga & Vinknes, Kathrine (2020). Postprandial effects of a meal low in sulfur amino acids and high in polyunsaturated fatty acids compared to a meal high in sulfur amino acids and saturated fatty acids on stearoyl CoA-desaturase indices and plasma sulfur amino acids: a pilot study. BMC Research Notes. 13. doi: 10.1186/s13104-020-05222-y. Full text in Research Archive Show summary

  Objective The sulfur amino acid (SAA) cysteine is positively related, whereas polyunsaturated fatty acids (PUFAs) are inversely related to activity of the lipogenic enzyme stearoyl-CoA desaturase (SCD). High SCD activity promotes obesity in animals, and plasma activity indices positively associates with fat mass in humans. SCD may thus be a target for dietary intervention with SAA restriction and PUFA enrichment with unknown potential benefits for body composition. We randomized ten healthy individuals to a meal restricted in SAAs and enriched with PUFAs (Cys/Metlow + PUFA) (n = 5) or a meal enriched in SAA and saturated fatty acids (Cys/Methigh + SFA) (n = 5). We measured plasma SCD activity indices (SCD16 and SCD18) and SAAs response hourly from baseline and up to 4 h postprandial. Results SCD16 was unchanged whereas SCD18 tended to increase in the Cys/Metlow + PUFA compared to the Cys/Methigh + SFA group (ptime*group interaction = 0.08). Plasma concentrations of total cysteine fractions including free and reduced cysteine decreased in the Cys/Metlow + PUFA compared to the Cys/Methigh + SFA group (both ptime*group interaction < 0.001). In conclusion, a meal low in SAA but high in PUFAs reduced plasma cysteine fractions but not SCD activity indices. This pilot study can be useful for the design and diet composition of future dietary interventions that targets SCD and SAA. Trial registration ClinicalTrials.gov: NCT02647970, registration date: 6 January 2016

• Elshorbagy, Amany; Graham, Ian & Refsum, Helga (2020). Body mass index determines the response of plasma sulfur amino acids to methionine loading. Biochimie. ISSN 0300-9084. 173, p. 107–113. doi: 10.1016/j.biochi.2020.03.001. Full text in Research Archive
• Olsen, Thomas; Sollie, Ove; Nurk, Eha; Turner, Cheryl; Jernerén, Fredrik & Ivy, John L. [Show all 10 contributors for this article] (2020). Exhaustive Exercise and Post-exercise Protein Plus Carbohydrate Supplementation Affect Plasma and Urine Concentrations of Sulfur Amino Acids, the Ratio of Methionine to Homocysteine and Glutathione in Elite Male Cyclists. Frontiers in Physiology. 11(2020). doi: 10.3389/fphys.2020.609335. Full text in Research Archive Show summary

  Plasma and tissue sulfur amino acid (SAA) availability are crucial for intracellular methylation reactions and cellular antioxidant defense, which are important processes during exercise and in recovery. In this randomized, controlled crossover trial among eight elite male cyclists, we explored the effect of exhaustive exercise and post-exercise supplementation with carbohydrates and protein (CHO+PROT) vs. carbohydrates (CHO) on plasma and urine SAAs, a potential new marker of methylation capacity (methionine/total homocysteine ratio [Met/tHcy]) and related metabolites. The purpose of the study was to further explore the role of SAAs in exercise and recovery. Athletes cycled to exhaustion and consumed supplements immediately after and in 30 min intervals for 120 min post-exercise. After ~18 h recovery, performance was tested in a time trial in which the CHO+PROT group cycled 8.5% faster compared to the CHO group (41:53 ± 1:51 vs. 45:26 ± 1:32 min, p

• Calderón-Larranãga, Amaia; Saadeh, Marguerita; Hooshmand, Babak; Refsum, Helga; Smith, A. David & Marengoni, Alessandra [Show all 7 contributors for this article] (2020). Association of Homocysteine, Methionine, and MTHFR 677C>T Polymorphism with Rate of Cardiovascular Multimorbidity Development in Older Adults in Sweden. JAMA Network Open. 3(5), p. 1–14. doi: 10.1001/jamanetworkopen.2020.5316. Full text in Research Archive
• Olsen, Thomas; Øvrebø, Bente; Yasein, Nadia Haj; Lee-Ødegård, Sindre; Svendsen, Karianne & Hjorth, Marit [Show all 11 contributors for this article] (2020). Effects of dietary methionine and cysteine restriction on plasma biomarkers, serum fibroblast growth factor 21, and adipose tissue gene expression in women with overweight or obesity: a double-blind randomized controlled pilot study. Journal of Translational Medicine. 18(122). doi: 10.1186/s12967-020-02288-x. Full text in Research Archive Show summary

  Background Dietary restriction of methionine and cysteine is a well-described model that improves metabolic health in rodents. To investigate the translational potential in humans, we evaluated the effects of dietary methionine and cysteine restriction on cardiometabolic risk factors, plasma and urinary amino acid profile, serum fibroblast growth factor 21 (FGF21), and subcutaneous adipose tissue gene expression in women with overweight and obesity in a double-blind randomized controlled pilot study. Methods Twenty women with overweight or obesity were allocated to a diet low (Met/Cys-low, n = 7), medium (Met/Cys-medium, n = 7) or high (Met/Cys-high, n = 6) in methionine and cysteine for 7 days. The diets differed only by methionine and cysteine content. Blood and urine were collected at day 0, 1, 3 and 7 and subcutaneous adipose tissue biopsies were taken at day 0 and 7. Results Plasma methionine and cystathionine and urinary total cysteine decreased, whereas FGF21 increased in the Met/Cys-low vs. Met/Cys-high group. The Met/Cys-low group had increased mRNA expression of lipogenic genes in adipose tissue including DGAT1. When we excluded one participant with high fasting insulin at baseline, the Met/Cys-low group showed increased expression of ACAC, DGAT1, and tendencies for increased expression of FASN and SCD1 compared to the Met/Cys-high group. The participants reported satisfactory compliance and that the diets were moderately easy to follow. Conclusions Our data suggest that dietary methionine and cysteine restriction may have beneficial effects on circulating biomarkers, including FGF21, and influence subcutaneous adipose tissue gene expression. These results will aid in the design and implementation of future large-scale dietary interventions with methionine and cysteine restriction. Trial registration ClinicalTrials.gov Identifier: NCT03629392, registration date: 14/08/2018 https://clinicaltrials.gov/ct2/show/NCT03629392.

• Henjum, Sigrun; Manger, Mari Skar; Hampel, Daniela; Brantsæter, Anne Lise; Shahab-Ferdows, Setareh & Bastani, Nasser Ezzatkhah [Show all 9 contributors for this article] (2020). Vitamin B12 concentrations in milk from Norwegian women during the six first months of lactation. European Journal of Clinical Nutrition. ISSN 0954-3007. 74(5), p. 749–756. doi: 10.1038/s41430-020-0567-x. Full text in Research Archive Show summary

  Background: Human milk vitamin B12 (B12) concentrations depend on maternal status and intake; only few data are available in high-income countries. Objective: We assessed human milk B12 concentrations during the first 6 months postpartum in Norwegian women and its association with maternal dietary B12 intake and maternal urinary methylmalonic acid (MMA) concentration. Methods: In this cross-sectional study, 175 mothers, exclusively (80%) or partially (20%) breastfeeding, were included. Milk B12 was measured by IMMULITE®/IMMULITE® 1000 B12 competitive protein binding assay and urinary MMA relative to creatinine (MMA/Cr) by liquid chromatography-tandem-mass spectrometry. Maternal habitual B12 intake and supplement use were estimated using a food frequency questionnaire. Results: Mean human milk B12 concentration was 327 pmol/L (range 140-1089), with 402 pmol/L at 1 month (n = 21), 333 pmol/L at four months (n = 32), and 299 pmol/L at 6 months (n = 21). Maternal B12 intake was 5 µg/d, 89% met the Estimated Average Requirement, and supplement use did not affect milk B12 concentrations. MMA/Cr was low in all women compared with published data. In exclusively breastfeeding women, MMA/Cr (beta (95% CI) -42.5 (-82.5, -2.5) and time since birth (-4.9 (-9.6, -0.3)) were significant predictors of human milk B12 concentrations. There was no association between total B12 intake and milk B12 concentration or between total B12 intake and MMA/Cr. Conclusions: Maternal B12 status and human milk B12 concentrations are likely sufficient, based on adequate maternal B12 dietary intake combined with low urinary MMA concentrations. Nevertheless, milk B12 concentration fell during 6 months postpartum while maternal B12 status did not change.

• Lee-Ødegård, Sindre; Gulseth, Hanne Løvdal; Langleite, Torgrim Mikal; Norheim, Frode; Olsen, Thomas & Refsum, Helga [Show all 9 contributors for this article] (2020). Branched-chain amino acid metabolism, insulin sensitivity and liver fat response to exercise training in sedentary dysglycaemic and normoglycaemic men. Diabetologia. ISSN 0012-186X. 64(2), p. 410–423. doi: 10.1007/s00125-020-05296-0. Full text in Research Archive Show summary

  Aims/hypothesis: Obesity and insulin resistance may be associated with elevated plasma concentration of branched-chain amino acids (BCAAs) and impaired BCAA metabolism. However, it is unknown whether the insulin-sensitising effect of long-term exercise can be explained by concomitant change in BCAAs and their metabolism. Methods: We included 26 sedentary overweight and normal-weight middle-aged men from the MyoGlu clinical trial, with or without dysglycaemia, for 12 weeks of supervised intensive exercise intervention, including two endurance and two resistance sessions weekly. Insulin sensitivity was measured as the glucose infusion rate (GIR) from a hyperinsulinaemic−euglycaemic clamp. In addition, maximum oxygen uptake, upper and lower body strength and adipose tissue depots (using MRI and spectroscopy) were measured, and subcutaneous white adipose tissue (ScWAT) and skeletal muscle (SkM) biopsies were harvested both before and after the 12 week intervention. In the present study we have measured plasma BCAAs and related metabolites using CG-MS/MS and HPLC-MS/MS, and performed global mRNA-sequencing pathway analysis on ScWAT and SkM. Results: In MyoGlu, men with dysglycaemia displayed lower GIR, more fat mass and higher liver fat content than normoglycaemic men at baseline, and 12 weeks of exercise increased GIR, improved body composition and reduced liver fat content similarly for both groups. In our current study we observed higher plasma concentrations of BCAAs (14.4%, p = 0.01) and related metabolites, such as 3-hydroxyisobutyrate (19.4%, p = 0.034) in dysglycaemic vs normoglycaemic men at baseline. Baseline plasma BCAA levels correlated negatively to the change in GIR (ρ = −0.41, p = 0.037) and VO2max (ρ = −0.47, p = 0.015) after 12 weeks of exercise and positively to amounts of intraperitoneal fat (ρ = 0.40, p = 0.044) and liver fat (ρ = 0.58, p = 0.01). However, circulating BCAAs and related metabolites did not respond to 12 weeks of exercise, with the exception of isoleucine, which increased in normoglycaemic men (10 μmol/l, p = 0.01). Pathway analyses of mRNA-sequencing data implied reduced BCAA catabolism in both SkM and ScWAT in men with dysglycaemia compared with men with normoglycaemia at baseline. Gene expression levels related to BCAA metabolism correlated positively with GIR and markers of mitochondrial content in both SkM and ScWAT, and negatively with fat mass generally, and particularly with intraperitoneal fat mass. mRNA-sequencing pathway analysis also implied increased BCAA metabolism after 12 weeks of exercise in both groups and in both tissues, including enhanced expression of the gene encoding branched-chain α-ketoacid dehydrogenase (BCKDH) and reduced expression of the BCKDH phosphatase in both groups and tissues. Gene expression of SLC25A44, which encodes a mitochondrial BCAA transporter, was increased in SkM in both groups, and gene expression of BCKDK, which encodes BCKDH kinase, was reduced in ScWAT in dysglycaemic men. Mediation analyses indicated a pronounced effect of enhanced SkM (~53%, p = 0.022), and a moderate effect of enhanced ScWAT (~18%, p = 0.018) BCAA metabolism on improved insulin sensitivity after 12 weeks of exercise, based on mRNA sequencing. In comparison, plasma concentration of BCAAs did not mediate any effect in this regard. Conclusion/interpretation: Plasma BCAA concentration was largely unresponsive to long-term exercise and unrelated to exercise-induced insulin sensitivity. On the other hand, the insulin-sensitising effect of long-term exercise in men may be explained by enhanced SkM and, to a lesser degree, also by enhanced ScWAT BCAA catabolism.

• Su, Yi; Elshorbagy, Amany; Turner, Cheryl; Refsum, Helga; Chan, Ruth & Kwok, Timothy (2019). Circulating amino acids are associated with bone mineral density decline and ten-year major osteoporotic fracture risk in older community-dwelling adults. Bone. ISSN 8756-3282. 129, p. 1–8. doi: 10.1016/j.bone.2019.115082. Full text in Research Archive
• Hanvold, Susanna; Vinknes, Kathrine; Løken, Elin Bjørge; Hjartåker, Anette; Klungsøyr, Ole & Birkeland, Eline [Show all 10 contributors for this article] (2019). Does Lifestyle Intervention After Gastric Bypass Surgery Prevent Weight Regain? A Randomized Clinical Trial. Obesity Surgery. ISSN 0960-8923. 29(11), p. 3419–3431. doi: 10.1007/s11695-019-04109-7. Full text in Research Archive
• Jernerén, Fredrik; Cederholm, Tommy; Refsum, Helga; Smith, A David; Turner, Cheryl & Palmblad, Jan [Show all 13 contributors for this article] (2019). Homocysteine status modifies the treatment effect of omega-3 fatty acids on cognition in a randomized clinical trial in mild to moderate Alzheimer's disease: The OmegAD Study. Journal of Alzheimer's Disease. ISSN 1387-2877. 69(1), p. 189–197. doi: 10.3233/JAD-181148. Full text in Research Archive
• Solvang, Stein-Erik Hafstad; Nordrehaug, Jan Erik; Tell, Grethe S.; Nygård, Ottar; Mccann, Adrian & Ueland, Per Magne [Show all 13 contributors for this article] (2019). The kynurenine pathway and cognitive performance in community-dwelling older adults. The Hordaland Health Study. Brain, Behavior, and Immunity. ISSN 0889-1591. 75, p. 155–162. doi: 10.1016/j.bbi.2018.10.003. Full text in Research Archive
• Lee-Ødegård, Sindre; Olsen, Thomas; Vinknes, Kathrine; Refsum, Helga; Gulseth, Hanne Løvdal & Birkeland, Kåre I. [Show all 7 contributors for this article] (2019). Plasma Sulphur-Containing Amino Acids, Physical Exercise and Insulin Sensitivity in Overweight Dysglycemic and Normal Weight Normoglycemic Men. Nutrients. 11(1). doi: 10.3390/nu11010010. Full text in Research Archive Show summary

  Plasma sulphur-containing amino acids and related metabolites are associated with insulin sensitivity, although the mechanisms are unclear. We examined the effect of exercise on this relationship. Dysglycemic (n = 13) and normoglycemic (n = 13) men underwent 45 min cycling before and after 12 weeks exercise intervention. We performed hyperinsulinemic euglycemic clamp, mRNA-sequencing of skeletal muscle and adipose tissue biopsies, and targeted profiling of plasma metabolites by LC-MS/MS. Insulin sensitivity increased similarly in dysglycemic and normoglycemic men after 12 weeks of exercise, in parallel to similar increases in concentration of plasma glutamine, and decreased concentrations of plasma glutamate, cysteine, taurine, and glutathione. Change in plasma concentrations of cysteine and glutathione exhibited the strongest correlations to exercise-improved insulin sensitivity, and expression of a cluster of genes essential for oxidative phosphorylation and fatty acid metabolism in both skeletal muscle and adipose tissue, as well as mitochondria-related genes such as mitofilin. Forty-five min of cycling decreased plasma concentrations of glutamine and methionine, and increased plasma concentrations of glutamate, homocysteine, cystathionine, cysteine, glutathione, and taurine. Similar acute responses were seen in both groups before and after the 12 weeks training period. Both acute and long-term exercise may influence transsulphuration and glutathione biosynthesis, linking exercise-improved insulin sensitivity to oxidative stress and mitochondrial function.

• Olsen, Thomas; Vinknes, Kathrine; Blomhoff, Rune; Lysne, Vegard; Midttun, Øivind & Dhar, Indu [Show all 12 contributors for this article] (2019). Creatinine, total cysteine and uric acid are associated with serum retinol in patients with cardiovascular disease. European Journal of Nutrition. ISSN 1436-6207. doi: 10.1007/s00394-019-02086-2. Full text in Research Archive Show summary

  Purpose: We hypothesized that biomarkers and dietary factors related to cardiovascular disease risk were associated with serum retinol and evaluated these potential associations in patients with suspected coronary artery disease (CAD). Methods: We used cross-sectional data from 4116 patients hospitalised for suspected CAD. Dietary data were obtained from a subgroup of 1962 patients using a food frequency questionnaire. Potential biomarkers and dietary factors were explored using linear regression modelling adjusted for age and sex. Regression coefficients and corresponding confidence intervals (CI) are given as % change in serum retinol per unit change in the predictors. Analyses were performed in the total population and in strata of serum retinol tertiles. Results: In age- and sex-adjusted models, serum creatinine (standardized β: 0.38, 95% CI [0.35, 0.42]), plasma total cysteine (0.26, [0.23, 0.29]), serum uric acid (0.30, [0.26, 0.33]) and plasma neopterin (0.22, [0.18, 0.25]) were positively associated, whereas plasma serine (− 0.15, [− 0.18, − 0.12]) and serum C-reactive protein (− 0.15, [− 0.18, − 0.12]) were inversely associated with serum retinol. When we included the significant biomarkers in a multivariate model, the model explained 33% of the variability (R2 = 0.33) in serum retinol. The results were similar in the lower and upper tertiles of serum retinol. Weak or no associations were observed for dietary factors. Conclusions: In patients with suspected CAD, concentrations of creatinine, cysteine and uric acid were positively associated with serum retinol. Future studies should assess whether retinol concentrations are influenced by metabolic alterations in patients at risk of cardiovascular disease.

• Hooshmand, Babak; Refsum, Helga; Smith, A David; Kalpouzos, Gregoria; Mangialasche, Francesca & Arnim, Christine A.F. Von [Show all 9 contributors for this article] (2019). Association of Methionine to Homocysteine Status With Brain Magnetic Resonance Imaging Measures and Risk of Dementia. JAMA psychiatry. ISSN 2168-6238. 76(11), p. 1198–1205. doi: 10.1001/jamapsychiatry.2019.1694. Full text in Research Archive Show summary

  The methionine to homocysteine status was associated with dementia development and structural brain changes during the 6-year study period, suggesting that a higher methionine to homocysteine ratio may be important in reducing the rate of brain atrophy and decreasing the risk of dementia in older adults.

• Olsen, Thomas; Øvrebø, Bente; Turner, Cheryl; Bastani, Nasser Ezzatkhah; Refsum, Helga & Vinknes, Kathrine (2018). Combining Dietary Sulfur Amino Acid Restriction with Polyunsaturated Fatty Acid Intake in Humans: A Randomized Controlled Pilot Trial. Nutrients. 10(12), p. 1–15. doi: 10.3390/nu10121822. Full text in Research Archive
• Smith, A. David; Refsum, Helga; Bottiglieri, Teodoro; Fenech, Michael; Hooshmand, Babak & McCaddon, Andrew [Show all 9 contributors for this article] (2018). Homocysteine and Dementia: An International Consensus Statement. Journal of Alzheimer's Disease. ISSN 1387-2877. 62(2), p. 561–570. doi: 10.3233/JAD-171042. Full text in Research Archive Show summary

  Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer’s disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.

• Allen, Lindsay H.; Miller, Joshua W.; Groot, Lisette de; Rosenberg, Irwin H.; Smith, A. David & Refsum, Helga [Show all 7 contributors for this article] (2018). Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review. Journal of Nutrition. ISSN 0022-3166. 148(4), p. 1995S–2027S. doi: 10.1093/jn/nxy201. Full text in Research Archive
• Olsen, Thomas; Vinknes, Kathrine; Svingen, Gard Frodahl Tveitevåg; Pedersen, Eva Ringdal; Dhar, Indu & Tell, Grethe S. [Show all 11 contributors for this article] (2018). The risk association of plasma total homocysteine with acute myocardial infarction is modified by serum vitamin A. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 25(15), p. 1612–1620. doi: 10.1177/2047487318788587. Full text in Research Archive Show summary

  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.

• Elshorbagy, Amany; Samocha-Bonet, D.; Jernerén, Fredrik; Turner, Cheryl; Refsum, Helga & Heilbronn, Leonie K. (2018). Food Overconsumption in Healthy Adults Triggers Early and Sustained Increases in Serum Branched-Chain Amino Acids and Changes in Cysteine Linked to Fat Gain. Journal of Nutrition. ISSN 0022-3166. 148(7), p. 1073–1080. doi: 10.1093/jn/nxy062. Full text in Research Archive
• Wanders, Anne J.; Alssema, Marjan; Hoon, Sabine E.M. De; Feskens, Edith J.M.; Woudenbergh, Geertruida J. van & Kallen, Carla J. Van Der [Show all 14 contributors for this article] (2018). Circulating Polyunsaturated Fatty Acids as Biomarkers for Dietary Intake across Subgroups: The CODAM and Hoorn Studies. Annals of Nutrition and Metabolism. ISSN 0250-6807. 72(2), p. 117–125. doi: 10.1159/000486244. Full text in Research Archive
• Sollie, Ove; Jeppesen, Per Bendix; Tangen, Daniel S.; Jernerén, Fredrik; Nellemann, Birgitte & Valsdottir, Thorhildur [Show all 12 contributors for this article] (2018). Protein intake in the early recovery period after exhaustive exercise improves performance the following day. Journal of applied physiology. ISSN 8750-7587. 125(6), p. 1731–1742. doi: 10.1152/japplphysiol.01132.2017. Full text in Research Archive Show summary

  The aim of the present study was to investigate the effect of protein and carbohydrate ingestion during early recovery from exhaustive exercise on performance after 18-h recovery. Eight elite cyclists (V̇o2max: 74.0 ± 1.6 ml·kg−1·min−1) completed two exercise and diet interventions in a double-blinded, randomized, crossover design. Participants cycled first at 73% of V̇o2max (W73%) followed by 1-min intervals at 90% of V̇o2max until exhaustion. During the first 2 h of recovery, participants ingested either 1.2 g carbohydrate·kg−1·h−1 (CHO) or 0.8 g carbohydrate + 0.4 g protein·kg−1·h−1 (CHO + PROT). The diet during the remaining recovery period was similar for both interventions and adjusted to body weight. After an 18-h recovery, cycling performance was assessed with a 10-s sprint test, 30 min of cycling at W73%, and a cycling time trial (TT). The TT was 8.5% faster (41:53 ± 1:51 vs. 45:26 ± 1:32 min; P < 0.03) after CHO + PROT compared with CHO. Mean power output during the sprints was 3.7% higher in CHO + PROT compared with CHO (1,063 ± 54 vs. 1,026 ± 53 W; P = 0.01). Nitrogen balance in the recovery period was negative in CHO and neutral in CHO + PROT (−82.4 ± 11.5 vs. 7.0 ± 15.4 mg/kg; P < 0.01). In conclusion, TT and sprint performances were improved 18 h after exhaustive cycling by CHO + PROT supplementation during the first 2 h of recovery compared with isoenergetic CHO supplementation. Our results indicate that intake of carbohydrate plus protein after exhaustive endurance exercise more rapidly converts the body from a catabolic to an anabolic state than carbohydrate alone, thus speeding recovery and improving subsequent cycling performance.

• Olsen, Thomas; Vinknes, Kathrine; Svingen, Gard Frodahl Tveitevåg; Pedersen, Eva Ringdal; Tell, Grethe S. & Blomhoff, Rune [Show all 11 contributors for this article] (2017). Cardiovascular disease risk associated with serum apolipoprotein B is modified by serum vitamin A. Atherosclerosis. ISSN 0021-9150. p. 325–330. doi: 10.1016/j.atherosclerosis.2017.07.020. Full text in Research Archive
• Jones, Simon Vann; Banerjee, Subimal; Smith, David; Refsum, Helga & Lennox, Belinda (2017). Elevated homocysteine and N-methyl-d-aspartate-receptor antibodies as a cause of behavioural and cognitive decline in 22q11.2 deletion syndrome. Oxford Medical Case Reports. 2017(12), p. 262–264. doi: 10.1093/omcr/omx076. Full text in Research Archive
• Vinknes, Kathrine; Nurk, Eha; Tell, Grethe S.; Sulo, Gerhard; Refsum, Helga & Elshorbagy, Amany K. (2017). The relation of CUN-BAE index and BMI with body fat, cardiovascular events and diabetes during a 6-year follow-up: The hordaland health study. Clinical Epidemiology. 9, p. 555–566. doi: 10.2147/CLEP.S145130. Full text in Research Archive
• Yasein, Nadia Haj; Berg, Ole; Jerneren, Fredrik; Refsum, Helga; Nebb, Hilde Irene & Dalen, Knut Tomas (2017). Cysteine deprivation prevents induction of peroxisome proliferator-activated receptor gamma-2 and adipose differentiation of 3T3-L1 cells. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1862(6), p. 623–635. doi: 10.1016/j.bbalip.2017.02.009. Full text in Research Archive
• Kumar, Tivendra; Taneja, Sunita; Sachdev, Harshpal S; Refsum, Helga; Yajnik, Chittaranjan S. & Bhandari, Nita [Show all 7 contributors for this article] (2017). Supplementation of vitamin B12 or folic acid on hemoglobin concentration in children 6-36 months of age: A randomized placebo controlled trial. Clinical Nutrition. ISSN 0261-5614. 36(4), p. 986–991. doi: 10.1016/j.clnu.2016.07.002. Full text in Research Archive
• Hanvold, Susanna; Vinknes, Kathrine; Bastani, Nasser Ezzatkhah; Turner, Cheryl; Løken, Elin Bjørge & Mala, Tom [Show all 8 contributors for this article] (2017). Plasma amino acids, adiposity, and weight change after gastric bypass surgery: are amino acids associated with weight regain? European Journal of Nutrition. ISSN 1436-6207. p. 1–9. doi: 10.1007/s00394-017-1533-9. Full text in Research Archive
• Holm, Maia Blomhoff; Bastani, Nasser Ezzatkhah; Holme, Ane Moe; Zucknick, Manuela; Jansson, Thomas & Refsum, Helga [Show all 10 contributors for this article] (2017). Uptake and release of amino acids in the fetal-placental unit in human pregnancies. PLOS ONE. 12(10). doi: 10.1371/journal.pone.0185760. Full text in Research Archive Show summary

  Objectives: The current concepts of human fetal-placental amino acid exchange and metabolism are mainly based on animal-, in vitro- and ex vivo models. We aimed to determine and assess the paired relationships between concentrations and arteriovenous differences of 19 amino acids on the maternal and fetal sides of the human placenta in a large study sample. Methods: This cross-sectional in vivo study included 179 healthy women with uncomplicated term pregnancies. During planned cesarean section, we sampled blood from incoming and outgoing vessels on the maternal (radial artery and uterine vein) and fetal (umbilical vein and artery) sides of the placenta. Amino acid concentrations were measured by liquid chromatography—tandem mass spectrometry. We calculated paired arteriovenous differences and performed Wilcoxon signed-rank tests and Spearman’s correlations. Results: In the umbilical circulation, we observed a positive venoarterial difference (fetal uptake) for 14 amino acids and a negative venoarterial difference (fetal release) for glutamic acid (p<0.001). In the maternal circulation, we observed a positive arteriovenous difference (uteroplacental uptake) for leucine (p = 0.005), isoleucine (p = 0.01), glutamic acid (p<0.001) and arginine (p = 0.04) and a negative arteriovenous difference (uteroplacental release) for tyrosine (p = 0.002), glycine (p = 0.01) and glutamine (p = 0.02). The concentrations in the maternal artery and umbilical vein were correlated for all amino acids except tryptophan, but we observed no correlations between the uteroplacental uptake and the fetal uptake or the umbilical vein concentration. Two amino acids showed a correlation between the maternal artery concentration and the fetal uptake. Conclusions: Our human in vivo study expands the current insight into fetal-placental amino acid exchange, and discloses some differences from what has been previously described in animals. Our findings are consistent with the concept that the fetal supply of amino acids in the human is the result of a dynamic interplay between fetal and placental amino acid metabolism and interconversions.

• Elshorbagy, Amany; Jernerén, Fredrik; Basta, Marianne; Basta, Caroline; Turner, Cheryl & Khaled, Maram [Show all 7 contributors for this article] (2017). Amino acid changes during transition to a vegan diet supplemented with fish in healthy humans. European Journal of Nutrition. ISSN 1436-6207. 56(5), p. 1953–1962. doi: 10.1007/s00394-016-1237-6. Full text in Research Archive
• Parr, Christine Louise; Magnus, Maria Christine; Karlstad, Øystein; Haugen, Alice Margaretha; Refsum, Helga & Ueland, Per Magne [Show all 11 contributors for this article] (2017). Maternal folate intake during pregnancy and childhood asthma in a population-based cohort. American Journal of Respiratory and Critical Care Medicine. ISSN 1073-449X. 195(2), p. 221–228. doi: 10.1164/rccm.201604-0788OC. Full text in Research Archive
• Melvær, Giil Lasse; Midttun, Øivind; Refsum, Helga; Ulvik, Arve; Advani, Rajiv & Smith, A. David [Show all 7 contributors for this article] (2017). Kynurenine pathway metabolites in Alzheimer's disease. Journal of Alzheimer's Disease. ISSN 1387-2877. 60(2), p. 495–504. doi: 10.3233/JAD-170485. Full text in Research Archive
• Cabout, Mieke; Alssema, Marjan; Nijpels, Giel; Stehouwer, Coen D.A.; Zock, Peter L. & Brouwer, Ingeborg A. [Show all 9 contributors for this article] (2016). Circulating linoleic acid and alpha-linolenic acid and glucose metabolism: the Hoorn Study. European Journal of Nutrition. ISSN 1436-6207. Published ahead of print. doi: 10.1007/s00394-016-1261-6. Full text in Research Archive
• Zhang, Weihua; Jernerén, Fredrik; Lehne, Benjamin C.; Chen, Ming-Huei; Luben, Robert N. & Johnston, Carole [Show all 19 contributors for this article] (2016). Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels. Thrombosis and Haemostasis. ISSN 0340-6245. 116(6), p. 1041–1049. doi: 10.1160/TH16-02-0151. Full text in Research Archive
• Hooshmand, Babak; Mangialasche, Francesca; Kalpouzos, Grégoria; Solomon, Alina; Kåreholt, Ingemar & Smith, A. David [Show all 14 contributors for this article] (2016). Association of Vitamin B&lt;sub&gt;12&lt;/sub&gt;, folate, and sulfur amino acids with brain magnetic resonance imaging measures in older adults a longitudinal population-based study. JAMA psychiatry. ISSN 2168-6238. 73(6), p. 606–613. doi: 10.1001/jamapsychiatry.2016.0274. Full text in Research Archive
• Smith, A. David & Refsum, Helga (2016). Homocysteine, B Vitamins, and Cognitive Impairment. Annual review of nutrition. ISSN 0199-9885. 36, p. 211–239. doi: 10.1146/annurev-nutr-071715-050947. Full text in Research Archive
• Elshorbagy, Amany K; Jernerén, Fredrik; Scudamore, Cheryl L.; McMurray, Fiona; Cater, Heather & Hough, Tertius [Show all 8 contributors for this article] (2016). Exploring the lean phenotype of glutathione-depleted mice: Thiol, amino acid and fatty acid profiles. PLOS ONE. 11(10). doi: 10.1371/journal.pone.0163214. Full text in Research Archive
• Elshorbagy, Amany K.; Jernerén, Fredrik; Samocha-Bonet, D.; Refsum, Helga & Heilbronn, L.K. (2016). Serum S-adenosylmethionine, but not methionine, increases in response to overfeeding in humans. Nutrition & Diabetes. 6. doi: 10.1038/nutd.2015.44. Full text in Research Archive
• Hanvold, Susanna; Løken, Elin Bjørge; Paus, Sofie Flottorp; Brisis, Eva Rustad de; Bjerkan, Kirsti & Refsum, Helga [Show all 7 contributors for this article] (2015). Great Health Benefits But No Change in Employment or Psychopharmaceutical Drug Use 2 Years After Roux-en-Y Gastric Bypass. Obesity Surgery. ISSN 0960-8923. 25(9), p. 1672–1679. doi: 10.1007/s11695-015-1583-0. Full text in Research Archive Show summary

  Abstract Background The aim was to examine health benefits and lifestyle factors after Roux-en-Y gastric bypass (RYGB). Methods Patients (n=165) were investigated 2 years after RYGB in relation to psychopharmaceutical drugs, employment status, type 2 diabetes mellitus (T2DM), hypertension, metabolic syndrome (MetS), body weight, physical activity (PA), and energy intake. Results Excess weight loss (EWL) was 71.4±20.6 %. Prevalence of T2DM, hypertension, and MetS was reduced (P<0.001 for all). There were no changes in the use of psychopharmaceutical drugs (20.6 vs. 18.8 %, P=0.549) or in the proportion of unemployed participants (37.7 vs. 33.3 %, P=0.189) from pre- to post-surgery. Eighty-three percent achieved EWL ≥50 %. These subjects had a lower presurgery BMI. We found no differences in the prevalence of hypertension, T2DM, and MetS pre-surgery, but the prevalence was lower after surgery compared with subjects with EWL <50 %. Conclusion RYGB induced remission of T2DM, hypertension, and MetS 2 years after surgery. The benefit was greatest in the group with EWL ≥50 %. Despite excellent weight loss, there was no change in the use of psychopharmaceutical drugs or proportion of unemployed participants.

• Oulhaj, Abderrahim; Jernerén, Fredrik; Refsum, Helga; Smith, A. David & Jager, Celeste A. de (2015). Omega-3 fatty acid status enhances the prevention of cognitive decline by B Vitamins in mild cognitive impairment. Journal of Alzheimer's Disease. ISSN 1387-2877. 50(2), p. 547–557. doi: 10.3233/JAD-150777. Full text in Research Archive
• Kvestad, Ingrid; Taneja, Sunita; Kumar, Tivendra; Hysing, Mari; Refsum, Helga & Yajnik, Chittaranjan S. [Show all 8 contributors for this article] (2015). Vitamin B12 and folic acid improve gross motor and problem-solving skills in young North Indian children: A randomized placebo-controlled trial. PLOS ONE. 10(6). doi: 10.1371/journal.pone.0129915. Full text in Research Archive Show summary

  Objectives Deficiencies of vitamin B12 and folate are associated with delayed development and neurological manifestations. The objective of this study was to measure the effect of daily supplementation of vitamin B12 and/or folic acid on development in young North Indian children. Methods In a randomized, double blind trial, children aged six to 30 months, received supplement with placebo or vitamin B12 and/or folic acid for six months. Children were allocated in a 1:1:1:1 ratio in a factorial design and in blocks of 16. We measured development in 422 children by the Ages and Stages Questionnaire 3rd ed. at the end of the intervention. Results Compared to placebo, children who received both vitamin B12 and folic acid had 0.45 (95% CI 0.19, 0.73) and 0.28 (95% CI 0.02, 0.54) higher SD-units in the domains of gross motor and problem solving functioning, respectively. The effect was highest in susceptible subgroups consisting of stunted children, those with high plasma homocysteine (> 10 μmol/L) or in those who were younger than 24 at end study. With the exception of a significant improvement on gross motor scores by vitamin B12 alone, supplementation of either vitamin alone had no effect on any of the outcomes. Conclusion Our findings suggest that supplementation of vitamin B12 and folic acid benefit development in North Indian Children. Trial Registration ClinicalTrials.gov NCT00717730

• Jernerén, Fredrik; Elshorbagy, Amany K.; Oulhaj, Abderrahim; Smith, Stephen M.; Refsum, Helga & Smith, A. David (2015). Brain atrophy in cognitively impaired elderly: The importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial. American Journal of Clinical Nutrition. ISSN 0002-9165. 102(1), p. 215–221. doi: 10.3945/ajcn.114.103283. Full text in Research Archive
• Strand, Tor; Taneja, Sunita; Kumar, Tivendra; Manger, Mari Skar; Refsum, Helga & Yajnik, Chittaranjan S. [Show all 7 contributors for this article] (2015). Vitamin B-12, folic acid, and growth in 6- to 30-month-old children: A randomized controlled trial. Pediatrics. ISSN 0031-4005. 135(4), p. e918–e926. doi: 10.1542/peds.2014-1848. Full text in Research Archive
• Yajnik, Chittaranjan S; Chandak, Giriraj R; Joglekar, Charudatta V; Katre, Prachi; Bhat, Dattatray S & Singh, Suraj N [Show all 12 contributors for this article] (2014). Maternal homocysteine in pregnancy and offspring birthweight: Epidemiological associations and Mendelian randomization analysis. International Journal of Epidemiology. ISSN 0300-5771. 43(5), p. 1487–1497. doi: 10.1093/ije/dyu132. Full text in Research Archive
• Ulak, Manjeswori; Chandyo, Ram Krishna; Adhikari, Ramesh K.; Sharma, Pushpa R.; Sommerfelt, Halvor & Refsum, Helga [Show all 7 contributors for this article] (2014). Cobalamin and folate status in 6 to 35 months old children presenting with acute diarrhea in Bhaktapur, Nepal. PLOS ONE. 9(3:e90097). doi: 10.1371/journal.pone.0090079. Full text in Research Archive Show summary

  Background: Cobalamin and folate are essential micronutrients and are important in DNA and RNA synthesis, cell proliferation, growth, hematopoiesis, and cognitive function. However, data on cobalamin and folate status are lacking particularly from young children residing in low and middle income countries. Objective: To measure cobalamin and folate status and identifies their predictors among 6 to 35 months old children presenting with acute diarrhea. Design: This was a cross-sectional study in 823 children presenting with acute diarrhea. We measured plasma cobalamin, folate, methylmalonic acid and total homocysteine who sought treatment for acute diarrhea between June 1998 and August 2000. Results: The mean (SD) plasma concentrations of cobalamin, folate, total homocysteine and methylmalonic acid were 206 (124) pmol/L, 55 (32) nmol/L, 11.4 (5.6) µmol/L and 0.79 (1.2) µmol/L, respectively. The prevalence of low plasma cobalamin (>150 pmol/L) was 41% but less than 2% (15) children had low folate concentration (>10 nmol/L). Plasma homocysteine and methylmalonic acid concentrations were negatively associated with cobalamin concentration but not associated with folate status. The prevalence of cobalamin deficiency was higher in breastfed than non-breastfed children (44% vs 24%; p =>0.001). The prevalence of hyperhomocysteinemia (<10 µmol/L) and elevated methylmalonic acid (<0.28 µmol/L) were 73% and 52%, respectively. In the regression analyses, the plasma cobalamin concentration was positively associated with age, and introduction of animal or formula milk. Conclusions: Our study indicated that poor cobalamin status was common particularly among breastfed children. Folate deficiency was virtually none existent. Possible consequences of cobalamin deficiency in young children need to be explored.

• Doets, EL; Ueland, Per Magne; Tell, Grethe S; Vollset, Stein Emil; Nygård, Ottar & Veer, Pieter van't [Show all 11 contributors for this article] (2014). Interactions between plasma concentrations of folate and markers of vitamin B12 status with cognitive performance in elderly people not exposed to folic acid fortification: the Hordaland Health Study. British Journal of Nutrition. ISSN 0007-1145. 111(6), p. 1085–1095. doi: 10.1017/S000711451300336X. Full text in Research Archive
• Rajagopalan, Priya; Refsum, Helga; Hua, Xue; Toga, Arthur W.; Jack, Clifford R. & Weiner, Michael W [Show all 7 contributors for this article] (2013). Mapping creatinine- and cystatin C-related white matter brain deficits in the elderly. Neurobiology of Aging. ISSN 0197-4580. 34(4), p. 1221–1230. doi: 10.1016/j.neurobiolaging.2012.10.022. Full text in Research Archive
• Douaud, Gwenaëlle; Refsum, Helga; Jager, Celeste de; Jacoby, Robin; Nichols, Thomas E & Smith, Stephen M. [Show all 7 contributors for this article] (2013). Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 110(23), p. 9523–9528. doi: 10.1073/pnas.1301816110. Full text in Research Archive
• Vinknes, Kathrine; Elshorbagy, Amany K.; Drevon, Christian A; Gjesdal, Clara Gram; Tell, Grethe S & Nygård, Ottar [Show all 8 contributors for this article] (2013). Evaluation of the body adiposity index in a caucasian population: the Hordaland Health Study. American Journal of Epidemiology. ISSN 0002-9262. 177(6), p. 586–592. doi: 10.1093/aje/kws271. Full text in Research Archive
• Strand, Tor A; Taneja, Sunita; Ueland, Per Magne; Refsum, Helga; Bahl, Rajiv & Schneede, Jørn [Show all 8 contributors for this article] (2013). Cobalamin and folate status predicts mental development scores in North Indian children 12-18 mo of age. American Journal of Clinical Nutrition. ISSN 0002-9165. 97(2), p. 310–317. doi: 10.3945/ajcn.111.032268. Full text in Research Archive
• Strand, Bjørn Heine; Langballe, Ellen Melbye; Hjellvik, Vidar; Handal, Marte; Næss, Øyvind & Knudsen, Gun Peggy [Show all 15 contributors for this article] (2013). Midlife vascular risk factors and their association with dementia deaths: Results from a Norwegian prospective study followed up for 35 years. Journal of Neurological Sciences. ISSN 1302-1664. 324(1-2), p. 124–130. doi: 10.1016/j.jns.2012.10.018. Full text in Research Archive
• Nurk, Eha; Refsum, Helga; Bjelland, Ingvar; Drevon, Christian A; Tell, Grethe S & Ueland, Per Magne [Show all 10 contributors for this article] (2013). Plasma free choline, betaine and cognitive performance: the Hordaland Health Study. British Journal of Nutrition. ISSN 0007-1145. 109(3), p. 511–519. doi: 10.1017/S0007114512001249. Full text in Research Archive Show summary

  Choline and betaine are nutrients involved in one-carbon metabolism. Choline is essential for neurodevelopment and brain function. We studied the associations between cognitive function and plasma concentrations of free choline and betaine. In a cross-sectional study, 2195 subjects (55 % women), aged 70–74 years, underwent extensive cognitive testing including the Kendrick Object Learning Test (KOLT), Trail Making Test (part A, TMT-A), modified versions of the Digit Symbol Test (m-DST), Block Design (m-BD), Mini-Mental State Examination (m-MMSE) and Controlled Oral Word Association Test (COWAT). Compared with low concentrations, high choline (>8·4 μmol/l) was associated with better test scores in the TMT-A (56·0 v. 61·5, P= 0·004), m-DST (10·5 v. 9·8, P= 0·005) and m-MMSE (11·5 v. 11·4, P= 0·01). A generalised additive regression model showed a positive dose–response relationship between the m-MMSE and choline (P= 0·012 from a corresponding linear regression model). Betaine was associated with the KOLT, TMT-A and COWAT, but after adjustments for potential confounders, the associations lost significance. Risk ratios (RR) for poor test performance roughly tripled when low choline was combined with either low plasma vitamin B12 ( ≤ 257 pmol/l) concentrations (RRKOLT= 2·6, 95 % CI 1·1, 6·1; RRm-MMSE= 2·7, 95 % CI 1·1, 6·6; RRCOWAT= 3·1, 95 % CI 1·4, 7·2) or high methylmalonic acid (MMA) ( ≥ 3·95 μmol/l) concentrations (RRm-BD= 2·8, 95 % CI 1·3, 6·1). Low betaine ( ≤ 31·1 μmol/l) combined with high MMA was associated with elevated RR on KOLT (RRKOLT= 2·5, 95 % CI 1·0, 6·2). Low plasma free choline concentrations are associated with poor cognitive performance. There were significant interactions between low choline or betaine and low vitamin B12 or high MMA on cognitive performance.

• Haj-Yasein, Nadia Nabil; Dalen, Knut Tomas; Berg, Ole; Bastani, Nasser Ezzatkhah; Refsum, Helga & Nebb, Hilde Irene (2013). Low Cysteine Interferes With PPARγ Activity And Reduces Adipocyte Differentiation. The Journal of Inherited Metabolic Disease (JIMD). ISSN 0141-8955. 36, p. S44–S44. doi: 10.1007/s10545-013-9631-1. Full text in Research Archive
• Taneja, Sunita; Strand, Tor A; Kumar, Tivendra; Mahesh, Madhu; Mohan, Sanjana & Manger, Mari Skar [Show all 9 contributors for this article] (2013). Folic acid and vitamin B-12 supplementation and common infections in 6-30-mo-old children in India: a randomized placebo-controlled trial. American Journal of Clinical Nutrition. ISSN 0002-9165. 98(3), p. 731–737. doi: 10.3945/ajcn.113.059592. Full text in Research Archive
• Reinders, Ilse; Ballegooijen, Adriana J. van; Visser, Marjolein; Elshorbagy, Amany K.; Refsum, Helga & Henry, Ronald M.A. [Show all 10 contributors for this article] (2013). Associations of serum n-3 and n-6 polyunsaturated fatty acids with echocardiographic measures among older adults: the Hoorn Study. European Journal of Clinical Nutrition. ISSN 0954-3007. 67(12), p. 1277–1283. doi: 10.1038/ejcn.2013.167. Full text in Research Archive
• Reinders, I; Ballegooijen, A J van; Visser, M; Elshorbagy, AK; Refsum, Helga & Henry, R.M.A. [Show all 10 contributors for this article] (2013). Low Cysteine Interferes With PPARγ Activity And Reduces Adipocyte Differentiation. European Journal of Clinical Nutrition. ISSN 0954-3007. doi: 10.1038/ejcn.2013.167. Full text in Research Archive
• Vinknes, Kathrine; Dekker, Jacqueline M.; Drevon, Christian A; Refsum, Helga; Nurk, Eha & Nijpels, Giel [Show all 13 contributors for this article] (2013). Plasma sulfur amino acids and stearoyl-CoA desaturase activity in two caucasian populations. Prostaglandins Leukot Essent Fatty Acids 2. Prostaglandins, Leukotrienes and Essential Fatty Acids. ISSN 0952-3278. 89(5), p. 297–303. doi: 10.1016/j.plefa.2013.09.007. Full text in Research Archive
• Vinknes, Kathrine; Elshorbagy, Amany K.; Drevon, Christian A; Nurk, Eha; Tell, Grethe S & Nygård, Ottar [Show all 8 contributors for this article] (2013). Associations between plasma polyunsaturated fatty acids, plasma stearoyl-CoA desaturase indices and body fat. Obesity. ISSN 1930-7381. 21(9), p. E512–E519. doi: 10.1002/oby.20457. Full text in Research Archive
• Elshorbagy, AK; Nijpels, G; Valdivia-Garcia, Maria; Stehouwer, C.D.A.; Ocké, Marga C & Refsum, Helga [Show all 7 contributors for this article] (2013). S-Adenosylmethionine Is Associated with Fat Mass and Trunkal Adiposity in Older Adults. Journal of Nutrition. ISSN 0022-3166. 143(12), p. 1982–1988. doi: 10.3945/jn.113.179192. Full text in Research Archive

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• Elshorbagy, Amany; Bastani, Nasser Ezzatkhah; Lee-Ødegård, Sindre; Øvrebø, Bente; Yasein, Nadia Haj & Svendsen, Karianne [Show all 10 contributors for this article] (2023). Correction to: The association of fasting plasma thiol fractions with body fat compartments, biomarker profile, and adipose tissue gene expression (Amino Acids, (2022), 10.1007/s00726-022-03229-2). Amino Acids. ISSN 0939-4451. 55, p. 547–548. doi: 10.1007/s00726-023-03244-x. Full text in Research Archive
• Bastani, Nasser Ezzatkhah; Refsum, Helga; Olsen, Thomas; Vinknes, Kathrine Jørgensen; Retterstøl, Kjetil & Zare, Hasse Khiabani (2022). Determination of plasma thiols using LC-MS/MS: Cysteine-lowering treatment with mesna against obesity: Preliminary results from a phase I dose-finding stud. Full text in Research Archive
• Smith, David; Sobczyńska-Malefora, Agata; Green, Ralph; Reynolds, Edward H & Refsum, Helga (2022). Mandatory food fortification with folic acid. The Lancet Global Health. ISSN 2572-116X. 10(10), p. e1389–e1389. doi: 10.1016/S2214-109X(22)00378-3. Full text in Research Archive
• Smith, A. David; Refsum, Helga & Miller, Joshua W. (2019). Dietary Supplements for Brain Health. Journal of the American Medical Association (JAMA). ISSN 0098-7484. 321(24), p. 2467–2467. doi: 10.1001/jama.2019.4963. Full text in Research Archive
• Refsum, Helga & Smith, A. David (2017). To the editor. JAMA pediatrics. ISSN 2168-6203. 171(7), p. 710–711. doi: 10.1001/jamapediatrics.2017.0866. Full text in Research Archive
• Smith, A. David; Refsum, Helga; Selhub, Jacob & Rosenberg, Irwin H. (2016). Decision on folic acid fortification in Europe must consider both risks and benefits. The BMJ. 352:i734, p. 1–2. doi: 10.1136/bmj.i734. Full text in Research Archive
• Smith, A. David; Refsum, Helga & Jacoby, Robin (2016). Evidence-based prevention and treatment of dementia. Lancet Neurology. ISSN 1474-4422. 15(10), p. 1005–1006. doi: 10.1016/S1474-4422(16)30074-6. Full text in Research Archive
• Smith, David A; Jager, Celeste A. de; Refsum, Helga & Rosenberg, Irwin H. (2015). Homocysteine lowering, B vitamins, and cognitive aging. American Journal of Clinical Nutrition. ISSN 0002-9165. 101(2), p. 415–416. doi: 10.3945/ajcn.114.098467. Full text in Research Archive
• Strand, Tor; Taneja, Sunita; Kumar, Tivendra; Manger, Mari Skar; Refsum, Helga & Yajnik, Chittaranjan S [Show all 7 contributors for this article] (2014). The Effect of Daily Vitamin B12 and Folic Acid Supplementation on Growth in 6-30 Month Old Children in India: A Randomized Controlled Trial. Full text in Research Archive
• Dalen, Knut Tomas; Haj-Yasein, Nadia Nabil; Berg, Ole; Refsum, Helga & Nebb, Hilde Irene (2014). Cysteine and adipocyte differentiation. Full text in Research Archive

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