Lipidome and inflammation interplay: the role of diet in this relationship.

PURPOSE OF REVIEW: The aim of this review was to provide an overview of the role of novel lipid biomarkers from the circulating lipidome in inflammatory processes and the impact that dietary patterns may have on the lipidome. RECENT FINDINGS: Inflammation is a process that underlies many acute and chronic diseases, contributing to their development and severity. Finding novel molecules which serve as biomarkers and which are involved in inflammation is very useful, since they offer us both preventive or therapeutic targets and reveal mechanisms of action. Recently, several studies have found circulating lipid molecules that are implicated in inflammatory processes of different diseases, such as cardiovascular diseases, type 2 diabetes, COVID-19 or other respiratory infectious diseases. As such, ceramides, triacylglicerides or lysophosphatidylcholines have been associated with inflammation in a different manner depending on the stage of inflammation. The study of dietary patterns, especially healthy ones as the Mediterranean or the Nordic diets, has shown the impact that dietary habits may have on the lipidomic profile of individuals. CONCLUSIONS: Healthy dietary patterns have been suggested to exert beneficial effects in the circulating lipid profile. Studying the circulating lipidome could help to find new biomarkers of underlying inflammation, especially in cases of chronic low-grade inflammatory diseases in which it is more difficult to detect.

Plasma metabolite profile of legume consumption and future risk of type 2 diabetes and cardiovascular disease.

BACKGROUND: Legume consumption has been linked to a reduced risk of type 2 diabetes (T2D) and cardiovascular disease (CVD), while the potential association between plasma metabolites associated with legume consumption and the risk of cardiometabolic diseases has never been explored. Therefore, we aimed to identify a metabolite signature of legume consumption, and subsequently investigate its potential association with the incidence of T2D and CVD. METHODS: The current cross-sectional and longitudinal analysis was conducted in 1833 PREDIMED study participants (mean age 67 years, 57.6% women) with available baseline metabolomic data. A subset of these participants with 1-year follow-up metabolomics data (n = 1522) was used for internal validation. Plasma metabolites were assessed through liquid chromatography-tandem mass spectrometry. Cross-sectional associations between 382 different known metabolites and legume consumption were performed using elastic net regression. Associations between the identified metabolite profile and incident T2D and CVD were estimated using multivariable Cox regression models. RESULTS: Specific metabolic signatures of legume consumption were identified, these included amino acids, cortisol, and various classes of lipid metabolites including diacylglycerols, triacylglycerols, plasmalogens, sphingomyelins and other metabolites. Among these identified metabolites, 22 were negatively and 18 were positively associated with legume consumption. After adjustment for recognized risk factors and legume consumption, the identified legume metabolite profile was inversely associated with T2D incidence (hazard ratio (HR) per 1 SD: 0.75, 95% CI 0.61-0.94; p = 0.017), but not with CVD incidence risk (1.01, 95% CI 0.86-1.19; p = 0.817) over the follow-up period. CONCLUSIONS: This study identified a set of 40 metabolites associated with legume consumption and with a reduced risk of T2D development in a Mediterranean population at high risk of cardiovascular disease. TRIAL REGISTRATION: ISRCTN35739639.

Telomere length and 4-year changes in cognitive function in an older Mediterranean population at high risk of cardiovascular disease.

BACKGROUND: Cognitive decline, a common process of brain ageing, has been associated with telomere length (TL). Delving into the identification of reliable biomarkers of brain ageing is essential to prevent accelerated cognitive impairment. METHODS: We selected 317 non-smoking 'Prevención con Dieta Mediterránea-Plus' (PREDIMED-Plus) participants (mean age, 65.8 ± 5.0 years) with metabolic syndrome from two trial centres who were following a lifestyle intervention. We measured TL and cognitive function at baseline and after 3 and 4 years of follow-up, respectively. Associations between baseline or 3-year changes in TL and baseline or 4-year changes in cognitive function were analysed using multivariable regression models. RESULTS: Baseline TL was not associated with baseline cognitive performance. Nevertheless, longer baseline TL was associated with improved 4-year changes in the Executive Function domain (ß: 0.29; 95%CI: 0.12 to 0.44; P < 0.001) and the Global Cognitive Function domain (ß: 0.19; 95%CI: 0.05 to 0.34; P = 0.010). Besides, a positive association was found between longer baseline TL and improved 4-year changes in the animal version of the Verbal Fluency Test (ß: 0.33; 95%CI: 0.12 to 0.52; P = 0.002). By contrast, 3-year changes in TL were not associated with changes in cognitive function after 4 years. CONCLUSIONS: Longer baseline TL could protect from cognitive decline and be used as a useful biomarker of brain ageing function in an older Mediterranean population at risk of cardiovascular disease and cognitive impairment.

Effects of Supplemented Mediterranean Diets on Plasma-Phospholipid Fatty Acid Profiles and Risk of Cardiovascular Disease after 1 Year of Intervention in the PREDIMED Trial.

BACKGROUND: Plasma fatty acids (FAs) have been associated with cardiovascular disease (CVD) risk. Diet and endogenous metabolism influence the FA profile of the plasma phospholipid (PL) fraction. In the PREDIMED trial, we examined 1-year changes in the FA profile of plasma PL according to a nutritional intervention with Mediterranean diets, either supplemented with extra-virgin olive oil (MedDiet + EVOO) or mixed nuts (MedDiet + nuts), in a high cardiovascular risk population. We also analyzed if 1-year changes in PL FAs were associated with subsequent cardiovascular risk. METHODS: We included 779 participants in our case-cohort study: 185 incident cases and 594 participants in the subcohort (including 31 overlapping cases). The end point was the incidence of CVD. We measured the FAs of plasma PL at baseline and after 1 year of intervention. RESULTS: MedDiet + EVOO increased C17:0 and C20:3n9 in linear regression models [ß coefficientperSD : 0.215 (95% CI, 0.032-0.399) and 0.271 (0.107-0.434), respectively] and decreased 16:1n7 and C22:4n6 [ßperSD: -0.239 (95% CI, -0.416 to -0.061) and -0.287 (95% CI, -0.460 to -0.113), respectively] vs the control group. MedDiet + nuts increased C18:3n3 [ßperSD: 0.382 (95% CI, 0.225 - 0.539)], C18:2n6 [ßper SD: 0.250 (95% CI, 0.073 - 0.428)], C18:0 [ßperSD: 0.268 (95% CI, 0.085-0.452)], and C22:0 [ßper SD: 0.216 (95% CI, 0.031-0.402)]; and decreased the sum of six n6 FAs [ßper SD: -0.147 (95% CI, -0.268 to -0.027)] vs the control group. The 1-year increase in C18:2n6 was inversely associated with the subsequent CVD risk (HRperSD: 0.64 (95% CI, 0.44-0.92)). CONCLUSIONS: MedDiet interventions changed n6 FAs and C16:1n7c; other changes were specific for each group: MedDiet + EVOO increased C17:0 and C20:3n9, and MedDiet + Nuts C18:3n3, C18:2n6, C18:0, and C22:0 FAs.

Olive oil consumption, plasma metabolites, and risk of type 2 diabetes and cardiovascular disease.

BACKGROUND: Olive oil consumption has been inversely associated with the risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, the impact of olive oil consumption on plasma metabolites remains poorly understood. This study aims to identify plasma metabolites related to total and specific types of olive oil consumption, and to assess the prospective associations of the identified multi-metabolite profiles with the risk of T2D and CVD. METHODS: The discovery population included 1837 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) trial with available metabolomics data at baseline. Olive oil consumption was determined through food-frequency questionnaires (FFQ) and adjusted for total energy. A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation sample. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known candidate metabolites and olive oil consumption were assessed using elastic net regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite-weighted models and FFQ-derived olive oil consumption in each pair of training-validation data sets within the discovery sample. We further estimated the prospective associations of the identified plasma multi-metabolite profile with incident T2D and CVD using multivariable Cox regression models. RESULTS: We identified a metabolomic signature for the consumption of total olive oil (with 74 metabolites), VOO (with 78 metabolites), and COO (with 17 metabolites), including several lipids, acylcarnitines, and amino acids. 10-CV Pearson correlation coefficients between total olive oil consumption derived from FFQs and the multi-metabolite profile were 0.40 (95% CI 0.37, 0.44) and 0.27 (95% CI 0.22, 0.31) for the discovery and validation sample, respectively. We identified several overlapping and distinct metabolites according to the type of olive oil consumed. The baseline metabolite profiles of total and extra virgin olive oil were inversely associated with CVD incidence (HR per 1SD: 0.79; 95% CI 0.67, 0.92 for total olive oil and 0.70; 0.59, 0.83 for extra virgin olive oil) after adjustment for confounders. However, no significant associations were observed between these metabolite profiles and T2D incidence. CONCLUSIONS: This study reveals a panel of plasma metabolites linked to the consumption of total and specific types of olive oil. The metabolite profiles of total olive oil consumption and extra virgin olive oil were associated with a decreased risk of incident CVD in a high cardiovascular-risk Mediterranean population, though no associations were observed with T2D incidence. TRIAL REGISTRATION: The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).

Plasma metabolite profiles associated with the World Cancer Research Fund/American Institute for Cancer Research lifestyle score and future risk of cardiovascular disease and type 2 diabetes.

BACKGROUND: A healthy lifestyle (HL) has been inversely related to type 2 diabetes (T2D) and cardiovascular disease (CVD). However, few studies have identified a metabolite profile associated with HL. The present study aims to identify a metabolite profile of a HL score and assess its association with the incidence of T2D and CVD in individuals at high cardiovascular risk. METHODS: In a subset of 1833 participants (age 55-80y) of the PREDIMED study, we estimated adherence to a HL using a composite score based on the 2018 Word Cancer Research Fund/American Institute for Cancer Research recommendations. Plasma metabolites were analyzed using LC-MS/MS methods at baseline (discovery sample) and 1-year of follow-up (validation sample). Cross-sectional associations between 385 known metabolites and the HL score were assessed using elastic net regression. A 10-cross-validation procedure was used, and correlation coefficients or AUC were assessed between the identified metabolite profiles and the self-reported HL score. We estimated the associations between the identified metabolite profiles and T2D and CVD using multivariable Cox regression models. RESULTS: The metabolite profiles that identified HL as a dichotomous or continuous variable included 24 and 58 metabolites, respectively. These are amino acids or derivatives, lipids, and energy intermediates or xenobiotic compounds. After adjustment for potential confounders, baseline metabolite profiles were associated with a lower risk of T2D (hazard ratio [HR] and 95% confidence interval (CI): 0.54, 0.38-0.77 for dichotomous HL, and 0.22, 0.11-0.43 for continuous HL). Similar results were observed with CVD (HR, 95% CI: 0.59, 0.42-0.83 for dichotomous HF and HR, 95%CI: 0.58, 0.31-1.07 for continuous HL). The reduction in the risk of T2D and CVD was maintained or attenuated, respectively, for the 1-year metabolomic profile. CONCLUSIONS: In an elderly population at high risk of CVD, a set of metabolites was selected as potential metabolites associated with the HL pattern predicting the risk of T2D and, to a lesser extent, CVD. These results support previous findings that some of these metabolites are inversely associated with the risk of T2D and CVD. TRIAL REGISTRATION: The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).

Correlation between serum advanced glycation end products and dietary intake of advanced glycation end products estimated from home cooking and food frequency questionnaires.

BACKGROUND & AIMS: To our knowledge the association between dietary advanced glycation end-products (dAGEs) and cardiometabolic disease is limited. Our aim was to examine the association between dAGEs and serum concentration of carboxymethyl-lysine (CML) or soluble receptor advanced glycation end-products (sRAGEs), and to assess the difference on dAGEs and circulating AGEs according to lifestyle and biochemical measures. METHODS AND RESULTS: 52 overweight or obese adults diagnosed with type 2 diabetes were included in this cross-sectional analysis. dAGEs were estimated from a Food Frequency Questionnaire (FFQ) or from a FFQ + Home Cooking Frequency Questionnaire (HCFQ). Serum concentrations of CML and sRAGEs were measured by ELISA. Correlation tests were used to analyze the association between dAGEs derived from the FFQ or FFQ + HCFQ and concentrations of CML or sRAGEs. Demographic characteristics, lifestyle factors and biochemical measures were analyzed according to sRAGEs and dAGEs using student t-test and ANCOVA. A significant inverse association was found between serum sRAGEs and dAGEs estimated using the FFQ + HCFQ (r = -0.36, p = 0.010), whereas no association was found for dAGEs derived from the FFQ alone. No association was observed between CML and dAGEs. dAGEs intake estimated from the FFQ + HCFQ was significantly higher among younger and male participants, and in those with higher BMI, higher Hb1Ac levels, longer time with type 2 diabetes, lower adherence to Mediterranean diet, and higher use of culinary techniques that generate more AGEs (all p values p < 0.05). CONCLUSIONS: These results show knowledge on culinary techniques is relevant to derive the association between dAGEs intake and cardiometabolic risk factors.

Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study.

BACKGROUND AND AIM: Plasma citric acid cycle (CAC) metabolites might be likely related to cardiovascular disease (CVD). However, studies assessing the longitudinal associations between circulating CAC-related metabolites and CVD risk are lacking. The aim of this study was to evaluate the association of baseline and 1-year levels of plasma CAC-related metabolites with CVD incidence (a composite of myocardial infarction, stroke or cardiovascular death), and their interaction with Mediterranean diet interventions. METHODS AND RESULTS: Case-cohort study from the PREDIMED trial involving participants aged 55-80 years at high cardiovascular risk, allocated to MedDiets or control diet. A subcohort of 791 participants was selected at baseline, and a total of 231 cases were identified after a median follow-up of 4.8 years. Nine plasma CAC-related metabolites (pyruvate, lactate, citrate, aconitate, isocitrate, 2-hydroxyglutarate, fumarate, malate and succinate) were measured using liquid chromatography-tandem mass spectrometry. Weighted Cox multiple regression was used to calculate hazard ratios (HRs). Baseline fasting plasma levels of 3 metabolites were associated with higher CVD risk, with HRs (for each standard deviation, 1-SD) of 1.46 (95%CI:1.20-1.78) for 2-hydroxyglutarate, 1.33 (95%CI:1.12-1.58) for fumarate and 1.47 (95%CI:1.21-1.78) for malate (p of linear trend <0.001 for all). A higher risk of CVD was also found for a 1-SD increment of a combined score of these 3 metabolites (HR = 1.60; 95%CI: 1.32-1.94, p trend <0.001). This result was replicated using plasma measurements after one-year. No interactions were detected with the nutritional intervention. CONCLUSION: Plasma 2-hydroxyglutarate, fumarate and malate levels were prospectively associated with increased cardiovascular risk. CLINICAL TRIAL NUMBER: ISRCTN35739639.

Factors associated with successful dietary changes in an energy-reduced Mediterranean diet intervention: a longitudinal analysis in the PREDIMED-Plus trial.

PURPOSE: Long-term nutrition trials may fail to respond to their original hypotheses if participants do not comply with the intended dietary intervention. We aimed to identify baseline factors associated with successful dietary changes towards an energy-reduced Mediterranean diet (MedDiet) in the PREDIMED-Plus randomized trial. METHODS: Longitudinal analysis of 2985 participants (Spanish overweight/obese older adults with metabolic syndrome) randomized to the active intervention arm of the PREDIMED-Plus trial. Dietary changes were assessed with a 17-item energy-reduced MedDiet questionnaire after 6 and 12 months of follow-up. Successful compliance was defined as dietary changes from baseline of ≥ 5 points for participants with baseline scores < 13 points or any increase if baseline score was ≥ 13 points. We conducted crude and adjusted multivariable logistic regression models to identify baseline factors related to compliance. RESULTS: Consistent factors independently associated with successful dietary change at both 6 and 12 months were high baseline perceived self-efficacy in modifying diet (OR6-month: 1.51, 95% CI 1.25-1.83; OR12-month: 1.66, 95% CI 1.37-2.01), higher baseline fiber intake (OR6-month: 1.62, 95% CI 1.07-2.46; OR12-month: 1.62, 95% CI 1.07-2.45), having > 3 chronic conditions (OR6-month: 0.65, 95% CI 0.53-0.79; OR12-month: 0.76, 95% CI 0.62-0.93), and suffering depression (OR6-month: 0.80, 95% CI 0.64-0.99; OR12-month: 0.71, 95% CI 0.57-0.88). CONCLUSION: Our results suggested that recruitment of individuals with high perceived self-efficacy to dietary change, and those who initially follow diets relatively richer in fiber may lead to greater changes in nutritional recommendations. Participants with multiple chronic conditions, specifically depression, should receive specific tailored interventions. TRIAL REGISTRATION: ISRCTN registry 89898870, 24th July 2014 retrospectively registered http://www.isrctn.com/ISRCTN89898870 .

Vitamin K dietary intake is associated with cognitive function in an older adult Mediterranean population.

BACKGROUND: In the last years, evidence that dietary vitamin K could have a role in the cognitive domain has increased. However, data from large trials are limited. The objective of this study was to assess the association of 2 year changes in the dietary intake of vitamin K with cognitive function measured through neuropsychological performance tests. METHODS: In 5,533 participants of the multicentre PREDIMED-Plus study (48.1% women, age 65.1 ± 4.9 years with overweight/obesity and metabolic syndrome), we assessed the adjusted odds ratios of cognitive function decline according to 2 year changes in vitamin K intake. Participants answered a battery of cognitive function tests and Food Frequency Questionnaires (FFQs) in order to estimate the vitamin K dietary intake. RESULTS: After adjusting for potential cofounders, the highest tertile of change of dietary vitamin K intake (median [IQR]; 194.4 µg/d [120.9, 373.1]) was inversely associated with a Mini-Mental State Examination (MMSE) score ≤24 (OR [95% CI]; 0.53 [0.35, 0.79] P for trend = 0.002) compared with a decrease in the intake of vitamin K (median [IQR]; -97.8 µg/d [-292.8, -51.5]). A significant positive association between changes in dietary vitamin K intake and the semantic verbal fluency test scores (OR [95% CI]; 0.69 [0.51, 0.94] P for trend = 0.019) was found. CONCLUSIONS: An increase of the intake of dietary vitamin K was associated with better cognitive function scores, independently of recognised risk factors for cognitive decline, in an older adult Mediterranean population with high cardiovascular risk.

Hypertension and changes in cognitive function in a Mediterranean population.

Background: Severe cognitive decline is one of the major public health problems in developed countries. Finding modifiable risk factors could become essential to develop strategies to prevent or delay dementia progression and stop its rising incidence.Objective: Our aim was to investigate the association between hypertension and cognitive function and to assess whether better adherence to the Mediterranean diet may modify this association.Methods: A subsample of 764 participants from the 'Seguimiento Universidad de Navarra' (SUN) cohort older than 55 years was evaluated with the Spanish Telephone Interview for Cognitive Status (TICS-m) at two-time points, separated by 6 years. Multivariable-adjusted linear regression models were used to prospectively assess the association between hypertension -also according to adherence to the Mediterranean diet- and 6-y changes in cognitive function.Results: The adjusted between-group difference in the 6-year change of the TICS-m score between hypertensive participants and their non-hypertensive counterparts was -0.36 (95% CI -0.70, -0.02). This association was stronger among participants with a lower adherence to the Mediterranean diet [-0.62 (95% CI: -1.09, -0.15)] but the differences between hypertensive and non-hypertensive participants were no longer significant among participants with a higher baseline adherence to the Mediterranean diet.Conclusion: In this Mediterranean cohort, hypertension was inversely associated with cognitive function, but an attenuation of this detrimental association by a moderate/high adherence to the Mediterranean diet was suggested.

Circulating Amino Acids and Risk of Peripheral Artery Disease in the PREDIMED Trial.

Effective prevention and risk prediction are important for peripheral artery disease (PAD) due to its poor prognosis and the huge disease burden it produces. Circulating amino acids (AA) and their metabolites may serve as biomarkers of PAD risk, but they have been scarcely investigated. The objective was to prospectively analyze the associations of baseline levels of plasma AA (and their pathways) with subsequent risk of PAD and the potential effect modification by a nutritional intervention with the Mediterranean diet (MedDiet). A matched case-control study was nested in the PREDIMED trial, in which participants were randomized to three arms: MedDiet with tree nut supplementation group, MedDiet with extra-virgin olive oil (EVOO) supplementation group or control group (low-fat diet). One hundred and sixty-seven PAD cases were matched with 250 controls. Plasma AA was measured with liquid chromatography/mass spectrometry at the Broad Institute. Baseline tryptophan, serine and threonine were inversely associated with PAD (ORfor 1 SD increase = 0.78 (0.61-0.99); 0.67 (0.51-0.86) and 0.75 (0.59-0.95), respectively) in a multivariable-adjusted conditional logistic regression model. The kynurenine/tryptophan ratio was directly associated with PAD (ORfor 1 SD increase = 1.50 (1.14-1.98)). The nutritional intervention with the MedDiet+nuts modified the association between threonine and PAD (p-value interaction = 0.018) compared with the control group. However, subjects allocated to the MedDiet+EVOO group were protected against PAD independently of baseline threonine. Plasma tryptophan, kynurenine/tryptophan ratio, serine and threonine might serve as early biomarkers of future PAD in subjects at a high risk of cardiovascular disease. The MedDiet supplemented with EVOO exerted a protective effect, regardless of baseline levels of threonine.

Walnut Consumption, Plasma Metabolomics, and Risk of Type 2 Diabetes and Cardiovascular Disease.

BACKGROUND: Walnut consumption is associated with lower risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unknown whether plasma metabolites related to walnut consumption are also associated with lower risk of cardiometabolic diseases. OBJECTIVES: The study aimed to identify plasma metabolites associated with walnut consumption and evaluate the prospective associations between the identified profile and risk of T2D and CVD. METHODS: The discovery population included 1833 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) study with available metabolomics data at baseline. The study population included 57% women (baseline mean BMI (in kg/m2): 29.9; mean age: 67 y). A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation population. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known metabolites and walnut consumption were assessed using elastic net continuous regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite weighted models and self-reported walnut consumption in each pair of training-validation data sets within the discovery population. We further estimated the prospective associations between the identified metabolite profile and incident T2D and CVD using multivariable Cox regression models. RESULTS: A total of 19 metabolites were significantly associated with walnut consumption, including lipids, purines, acylcarnitines, and amino acids. Ten-CV Pearson correlation coefficients between self-reported walnut consumption and the plasma metabolite profile were 0.16 (95% CI: 0.11, 0.20) in the discovery population and 0.15 (95% CI: 0.10, 0.20) in the validation population. The metabolite profile was inversely associated with T2D incidence (HR per 1 SD: 0.83; 95% CI: 0.71, 0.97; P = 0.02). For CVD incidence, the HR per 1-SD was 0.71 (95% CI: 0.60, 0.85; P < 0.001). CONCLUSIONS: A metabolite profile including 19 metabolites was associated with walnut consumption and with a lower risk of incident T2D and CVD in a Mediterranean population at high cardiovascular risk.

Plasma Metabolomic Profiles of Glycemic Index, Glycemic Load, and Carbohydrate Quality Index in the PREDIMED Study.

BACKGROUND: The quality of carbohydrate consumed, assessed by the glycemic index (GI), glycemic load (GL), or carbohydrate quality index (CQI), affects the postprandial glycemic and insulinemic responses, which have been implicated in the etiology of several chronic diseases. However, it is unclear whether plasma metabolites involved in different biological pathways could provide functional insights into the role of carbohydrate quality indices in health. OBJECTIVES: We aimed to identify plasma metabolomic profiles associated with dietary GI, GL, and CQI. METHODS: The present study is a cross-sectional analysis of 1833 participants with overweight/obesity (mean age = 67 y) from 2 case-cohort studies nested within the PREDIMED (Prevención con Dieta Mediterránea) trial. Data extracted from validated FFQs were used to estimate the GI, GL, and CQI. Plasma concentrations of 385 metabolites were profiled with LC coupled to MS and associations of these metabolites with those indices were assessed with elastic net regression analyses. RESULTS: A total of 58, 18, and 57 metabolites were selected for GI, GL, and CQI, respectively. Choline, cotinine, γ-butyrobetaine, and 36:3 phosphatidylserine plasmalogen were positively associated with GI and GL, whereas they were negatively associated with CQI. Fructose-glucose-galactose was negatively and positively associated with GI/GL and CQI, respectively. Consistent associations of 21 metabolites with both GI and CQI were found but in opposite directions. Negative associations of kynurenic acid, 22:1 sphingomyelin, and 38:6 phosphatidylethanolamine, as well as positive associations of 32:1 phosphatidylcholine with GI and GL were also observed. Pearson correlation coefficients between GI, GL, and CQI and the metabolomic profiles were 0.30, 0.22, and 0.27, respectively. CONCLUSIONS: The GI, GL, and CQI were associated with specific metabolomic profiles in a Mediterranean population at high cardiovascular disease risk. Our findings may help in understanding the role of dietary carbohydrate indices in the development of cardiometabolic disorders. This trial was registered at isrctn.com as ISRCTN35739639.

Polyphenol intake and cognitive decline in the Seguimiento Universidad de Navarra (SUN) Project.

The global growing rates of cognitive decline and dementia, together with the absence of curative therapies for these conditions, support the interest in researching potential primary prevention interventions, with particular focus on dietary habits. The aim was to assess the association between polyphenol intake and 6-year change in cognitive function in the 'Seguimiento Universidad de Navarra' (SUN) Project, a Spanish prospective cohort study. Changes (final - initial) in cognitive function were evaluated in a subsample of 806 participants (mean age 66 (sd 5) years, 69·7 % male) of the SUN Project using the validated Spanish Telephone Interview for Cognitive Status-modified score. Polyphenol intake was derived from a validated semi-quantitative FFQ and matching food composition data from the Phenol-Explorer database. Multivariable linear regression models were used to evaluate the association between total polyphenol intake, polyphenol subclasses and cognitive changes. No significant association between total polyphenol intake and changes in cognitive function was found. However, a higher intake of lignans (ßQuintile (Q) 5 v. Q1 0·81; 95 % CI 0·12, 1·51; Ptrend = 0·020) and stilbenes (ßQ5 v. Q1 0·82; 95 % CI 0·15, 1·49; Ptrend = 0·028) was associated with more favourable changes in cognitive function over time, particularly with respect to immediate memory and language domains. Olive oil and nuts were the major sources of variability in lignan intake, and wine in stilbene intake. The results suggest that lignan and stilbene intake was associated with improvements in cognitive function.

Association between coffee consumption and total dietary caffeine intake with cognitive functioning: cross-sectional assessment in an elderly Mediterranean population.

PURPOSE: Coffee is rich in compounds such as polyphenols, caffeine, diterpenes, melanoidins and trigonelline, which can stimulate brain activity. Therefore, the possible association of coffee consumption with cognition is of considerable research interest. In this paper, we assess the association of coffee consumption and total dietary caffeine intake with the risk of poor cognitive functioning in a population of elderly overweight/obese adults with metabolic syndrome (MetS). METHODS: PREDIMED-plus study participants who completed the Mini-Mental State Examination test (MMSE) (n = 6427; mean age = 65 ± 5 years) or a battery of neuropsychological tests were included in this cross-sectional analysis. Coffee consumption and total dietary caffeine intake were assessed at baseline using a food frequency questionnaire. Logistic regression models were fitted to evaluate the association between total, caffeinated and decaffeinated coffee consumption or total dietary caffeine intake and cognitive impairment. RESULTS: Total coffee consumers and caffeinated coffee consumers had better cognitive functioning than non-consumers when measured by the MMSE and after adjusting for potential confounders (OR 0.63; 95% CI 0.44-0.90 and OR 0.56; 95% CI 0.38-0.83, respectively). Results were similar when cognitive performance was measured using the Clock Drawing Test (CDT) and Trail Making Test B (TMT-B). These associations were not observed for decaffeinated coffee consumption. Participants in the highest tertile of total dietary caffeine intake had lower odds of poor cognitive functioning than those in the reference tertile when screened by the MMSE (OR 0.64; 95% CI 0.47-0.87) or other neurophysiological tests evaluating a variety of cognitive domains (i.e., CDT and TMT-A). CONCLUSIONS: Coffee consumption and total dietary caffeine intake were associated with better cognitive functioning as measured by various neuropsychological tests in a Mediterranean cohort of elderly individuals with MetS. TRIAL REGISTRATION: ISRCTN89898870. Registration date: July 24, 2014.

Psychological and metabolic risk factors in older adults with a previous history of eating disorder: A cross-sectional study from the Predimed-Plus study.

GOALS: To explore affective and cognitive status, later in life, in individuals with and without previous history of eating disorder (ED), and also its association with higher risk for metabolic syndrome (MetS) symptomatology. METHODS: A cross-sectional analysis of 6756 adults, aged 55-75 years with overweight/obesity and MetS participating in the Predimed-Plus study was conducted. Participants completed self-reported questionnaires to examine lifetime history of ED, according to DSM-5 criteria, and other psychopathological and neurocognitive factors. Anthropometric and metabolic measurements were also collected. RESULTS: Of the whole sample, 24 individuals (0.35%) reported a previous history of ED. In this subsample, there were more women and singles compared to their counterparts, but they also presented higher levels of depressive symptoms and higher cognitive impairment, but also higher body mass index (BMI) and severe obesity, than those without lifetime ED. CONCLUSIONS: This is one of the first studies to analyse the cognitive and metabolic impact of a previous history of ED. The results showed that previous ED was associated with greater affective and cognitive impairment, but also with higher BMI, later in life. No other MetS risk factors were found, after controlling for relevant variables.

High Plasma Glutamate and a Low Glutamine-to-Glutamate Ratio Are Associated with Increased Risk of Heart Failure but Not Atrial Fibrillation in the Prevención con Dieta Mediterránea (PREDIMED) Study.

BACKGROUND: Although the association between glutamate and glutamine in relation to cardiometabolic disorders has been evaluated, the role of these metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unknown. OBJECTIVES: We examined associations of glutamate, glutamine, and the glutamine-to-glutamate ratio with AF and HF incidence in a Mediterranean population at high cardiovascular disease (CVD) risk. METHODS: The present study used 2 nested case-control studies within the PREDIMED (Prevención con Dieta Mediterránea) study. During ∼10 y of follow-up, there were 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma concentrations of glutamate and glutamine were semiquantitatively profiled with LC-tandem MS. ORs were estimated with multivariable conditional logistic regression models. RESULTS: In fully adjusted models, per 1-SD increment, glutamate was associated with a 29% (95% CI: 1.08, 1.54) increased risk of HF and glutamine-to-glutamate ratio with a 20% (95% CI: 0.67, 0.94) decreased risk. Glutamine-to-glutamate ratio was also inversely associated with HF risk (OR per 1-SD increment: 0.80; 95% CI: 0.67, 0.94) when comparing extreme quartiles. Higher glutamate concentrations were associated with a worse cardiometabolic risk profile, whereas a higher glutamine-to-glutamate ratio was associated with a better cardiometabolic risk profile. No associations between the concentrations of these metabolites and AF were observed. CONCLUSIONS: Our findings suggest that high plasma glutamate concentrations possibly resulting from alterations in the glutamate-glutamine cycle may contribute to the development of HF in Mediterranean individuals at high CVD risk.This trial was registered at www.isrctn.com as ISRCTN35739639.

"A priori" Dietary Patterns and Cognitive Function in the SUN Project.

OBJECTIVES: To study and compare associations of 5 dietary patterns - Mediterranean dietary pattern (MDP), Dietary Approaches to Stop Hypertension (DASH), Mediterranean-DASH Intervention for Neurodegenerative delay (MIND), Alternative Healthy Eating Index (AHEI-2010), and a pro-vegetarian diet (PVD) - with cognitive function. PATIENTS AND METHODS: A subgroup of 806 participants from the "Seguimiento Universidad de Navarra"(SUN) cohort of university graduates, >55 years old, was interviewed with the validated Spanish Telephone Interview for Cognitive Status (STICS-m) at baseline and after 2 and 6 years. For recruitment to the SUN cohort, participants completed a validated food-frequency questionnaire to calculate dietary adherence scores. These scores were used as independent variables in linear regression models (a model for each dietary pattern) to assess their association with the 6-year change in STICS-m as the dependent variable. Linear mixed models were also fitted to compare trajectories of STICS-m scores. All models were adjusted for relevant confounding factors. RESULTS: Adjusted differences showed advantages in the 6-year change in STICS-m score of 0.25 (95% CI 0.04-0.45) for an increase of 1-SD (9 points) in the AHEI-2010 and of 0.27 (95% CI 0.05-0.48) for an increase of 1-SD (1.5 points) in the MIND diet. The MDP, DASH, and PVD scores yielded positive differences in their point estimates for an increase in 1-SD, but results were not statistically significant. The MIND diet appeared to modify changes in cognitive function over time. CONCLUSIONS: Our results showed a beneficial association between the MIND diet and cognitive function and suggested a benefit for the AHEI-2010 pattern. Results for the MDP, DASH, and PVD were inconclusive.

Association Between Fatty Acids of Blood Cell Membranes and Incidence of Coronary Heart Disease.

Objective- To examine the associations between baseline levels of fatty acids in blood cell membranes and their 1-year changes with the incidence of coronary heart disease (CHD) in older adults at high cardiovascular disease risk. Approach and Results- This is a case-control study nested in the PREDIMED trial (Prevención con Dieta Mediterránea), with 136 CHD cases and 272 controls (matched on age, sex, body mass index, intervention group, and time of permanence in the study to the time event). We used gas chromatography to measure the proportion of 22 fatty acids in blood cell membranes at baseline and after 1 year. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs. After adjustment for classical CHD risk factors and multiple testing, 1 SD increase in baseline levels of C22:0, C24:0 and the sum of individual very long chain saturated fatty acids was associated with 56% (OR, 0.44 [95% CI, 0.28-0.69]), 59% (OR, 0.41 [95% CI, 0.25-0.65]), and 55% (OR, 0.45 [95% CI, 0.29-0.70]) a decreased odds of developing CHD, respectively. Baseline C20:1n9 was associated with higher odds of CHD (OR, 1.58 [95% CI, 1.25-2.00]). Conclusions- Higher levels of C22:0 and C24:0 were associated with a lower CHD incidence, whereas higher levels of C20:1n9 were associated with a higher risk. This study adds to the growing body of evidence suggesting potential differences in the cardiovascular disease effects of different types of circulating saturated fatty acids.