Effect of 1-year lifestyle intervention with energy-reduced Mediterranean diet and physical activity promotion on the gut metabolome and microbiota: a randomized clinical trial.

BACKGROUND: The health benefits of the Mediterranean diet (MedDiet) have been linked to the presence of beneficial gut microbes and related metabolites. However, its impact on the fecal metabolome remains poorly understood. OBJECTIVES: Our goal was to investigate the weight-loss effects of a 1-y lifestyle intervention based on an energy-reduced MedDiet coupled with physical activity (intervention group), compared with an ad libitum MedDiet (control group), on fecal metabolites, fecal microbiota, and their potential association with cardiovascular disease risk factors. METHODS: A total of 400 participants (200 from each study group), aged 55-75 y, and at high cardiovascular disease risk, were included. Dietary and lifestyle information, anthropometric measurements, blood biochemical parameters, and stool samples were collected at baseline and after 1 y of follow-up. Liquid chromatography-tandem mass spectrometry was used to profile endogenous fecal metabolites, and 16S amplicon sequencing was employed to profile the fecal microbiota. RESULTS: Compared with the control group, the intervention group exhibited greater weight loss and improvement in various cardiovascular disease risk factors. We identified intervention effects on 4 stool metabolites and subnetworks primarily composed of bile acids, ceramides, and sphingosines, fatty acids, carnitines, nucleotides, and metabolites of purine and the Krebs cycle. Some of these were associated with changes in several cardiovascular disease risk factors. In addition, we observed a reduction in the abundance of the genera Eubacterium hallii group and Dorea, and an increase in alpha diversity in the intervention group after 1 y of follow-up. Changes in the intervention-related microbiota profiles were also associated with alterations in different fecal metabolite subnetworks and some cardiovascular disease risk factors. CONCLUSIONS: An intervention based on an energy-reduced MedDiet and physical activity promotion, compared with an ad libitum MedDiet, was associated with improvements in cardiometabolic risk factors, potentially through modulation of the fecal microbiota and metabolome. This trial was registered at https://www.isrctn.com/ as ISRCTN89898870 (https://doi.org/10.1186/ISRCTN89898870).

Adherence to the Mediterranean diet and nuclear magnetic resonance spectroscopy biomarkers in older individuals at high cardiovascular disease risk: cross-sectional and longitudinal analyses.

BACKGROUND: The Mediterranean diet (MedDiet) has been related to a decreased risk of cardiovascular disease (CVD) and diabetes. OBJECTIVES: We aimed to prospectively assess the relationship between adherence to the MedDiet and advanced lipoprotein subclass profiles and glucose metabolism and inflammation markers, as determined by nuclear magnetic resonance (NMR) spectroscopy. DESIGN: We conducted cross-sectional and longitudinal analyses within the framework of the PREvención con DIeta MEDiterránea study in 196 participants from the Reus-Tarragona center. Adherence to the MedDiet was assessed using a 14-item validated questionnaire [Mediterranean Diet Adherence Score (MEDAS)]. Plasma lipoprotein subclasses and molecular metabolite profiles were determined using NMR spectra collected on a Vantera Clinical Analyzer at baseline and after 1 y of follow-up. Baseline and 1-y categories of MEDAS were related to measures of lipoprotein atherogenicity and diabetes risk using multivariable-adjusted analysis of covariance models. RESULTS: Compared with participants in the lowest category of baseline MEDAS, those in the highest category showed higher concentrations of total high-density lipoprotein (HDL) particles and H1P HDL, lower concentrations of very low-density lipoprotein (VLDL)-triglyceride, smaller size of VLDL, and lower concentrations of very large VLDL, as well as lower concentrations of branched-chain amino acids, leucine, and GlycA and reduced Diabetes Risk Index (DRI) scores. In addition, participants who increased by 3 or more points in their 1-y MEDAS showed an increase in concentrations of H7P-HDL, H5P-HDL, and citrate, and reduced acetone and DRI scores compared with those with lesser adherence increases. CONCLUSIONS: In older adults at high cardiometabolic risk, higher MEDAS was associated with modest beneficial changes in lipoprotein and glucose metabolism. The results suggest that lipoprotein subclass distribution and glycemic control are potential mechanisms behind the well-known salutary effects of MedDiet on CVD and diabetes risk. Future clinical trials exploring the effects of the MedDiet on advanced lipoprotein subclass profiles and glucose metabolism markers are needed to confirm the results of our study. TRIAL REGISTRATION NUMBER: This trial was registered at controlled-trials.com as ISRCTN35739639.

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).

An Energy-Reduced Mediterranean Diet, Physical Activity, and Body Composition: An Interim Subgroup Analysis of the PREDIMED-Plus Randomized Clinical Trial.

Importance: Strategies targeting body composition may help prevent chronic diseases in persons with excess weight, but randomized clinical trials evaluating lifestyle interventions have rarely reported effects on directly quantified body composition. Objective: To evaluate the effects of a lifestyle weight-loss intervention on changes in overall and regional body composition. Design, Setting, and Participants: The ongoing Prevención con Dieta Mediterránea-Plus (PREDIMED-Plus) randomized clinical trial is designed to test the effect of the intervention on cardiovascular disease prevention after 8 years of follow-up. The trial is being conducted in 23 Spanish research centers and includes men and women (age 55-75 years) with body mass index between 27 and 40 and metabolic syndrome. The trial reported herein is an interim subgroup analysis of the intermediate outcome body composition after 3-year follow-up, and data analysis was conducted from February 1 to November 30, 2022. Of 6874 total PREDIMED-Plus participants, a subsample of 1521 individuals, coming from centers with access to a dual energy x-ray absorptiometry device, underwent body composition measurements at 3 time points. Intervention: Participants were randomly allocated to a multifactorial intervention based on an energy-reduced Mediterranean diet (MedDiet) and increased physical activity (PA) or to a control group based on usual care, with advice to follow an ad libitum MedDiet, but no physical activity promotion. Main Outcomes and Measures: The outcomes (continuous) were 3-year changes in total fat and lean mass (expressed as percentages of body mass) and visceral fat (in grams), tested using multivariable linear mixed-effects models. Clinical relevance of changes in body components (dichotomous) was assessed based on 5% or more improvements in baseline values, using logistic regression. Main analyses were performed in the evaluable population (completers only) and in sensitivity analyses, multiple imputation was performed to include data of participants lost to follow-up (intention-to-treat analyses). Results: A total of 1521 individuals were included (mean [SD] age, 65.3 [5.0] years; 52.1% men). In comparison with the control group (n=761), participants in the intervention arm (n=760) showed greater reductions in the percentage of total fat (between group differences after 1-year, -0.94% [95% CI, -1.19 to -0.69]; 3 years, -0.38% [95% CI, -0.64 to -0.12] and visceral fat storage after 1 year, -126 g [95% CI, -179 to -73.3 g]; 3 years, -70.4 g [95% CI, -126 to -15.2 g] and greater increases in the percentage of total lean mass at 1 year, 0.88% [95% CI, 0.63%-1.12%]; 3-years 0.34% [95% CI, 0.09%-0.60%]). The intervention group was more likely to show improvements of 5% or more in baseline body components (absolute risk reduction after 1 year, 13% for total fat mass, 11% for total lean mass, and 14% for visceral fat mass; after 3-years: 6% for total fat mass, 6% for total lean mass, and 8% for visceral fat mass). The number of participants needed to treat was between 12 and 17 to attain at least 1 individual with possibly clinically meaningful improvements in body composition. Conclusions and Relevance: The findings of this trial suggest a weight-loss lifestyle intervention based on an energy-reduced MedDiet and physical activity significantly reduced total and visceral fat and attenuated age-related losses of lean mass in older adults with overweight or obesity and metabolic syndrome. Continued follow-up is warranted to confirm the long-term consequences of these changes on cardiovascular clinical end points. Trial Registration: isrctn.org Identifier: ISRCTN89898870.

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).

Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome.

Cognitive impairment is present in a broad spectrum of medical conditions and in aging. Here, we aimed to identify plasma proteins related to cognitive function in a sample of older adults with overweight/obesity and metabolic syndrome. A total of 129 subjects (mean age 64.7 years; 36% females) were grouped according to low (l-GCF, N=65) or high (h-GCF, N=64) global cognitive function and matched according to education, sex, age, and body mass index. Cognitive performance was assessed using neuropsychological tests. Plasma levels of 92 neurology-related proteins were assessed using a proximity extension assay. An elastic net regression analysis was used to identify proteins more associated with cognitive performance. Additionally, the protein expression levels were compared between the two groups by means of a t-test with false discovery rate correction. Pearson correlations were used to assess associations between the protein levels and scores from the neurocognitive tests. Six proteins (alpha-2-MRAP, HAGH, Siglec-9, MDGA1, IL12, and EDA2R) were identified as potential contributors to cognitive performance, remaining significantly increased in l-GCF compared to h-GCF participants after correction for multiple testing. Negative correlations (r= -0.23 to -0.18, i.e., lower protein levels, higher cognitive function) were found between global cognitive function and Siglec-9, NMNAT1, HAGH, LXN, gal-8, alpha-2-MRAP, IL12, PDGF-R-alpha, NAAA, EDA2R, CLEC1B, and LAT. Mini-mental state examination z scores showed the strongest correlations with protein levels, specifically negative correlations with CLEC1b, LXN, LAT, PLXNB3, NMNAT1, gal-8, HAGH, NAAA, CTSS, EZR, KYNU, MANF (r=-0.38 to -0.26) and a positive correlation with ADAM23 (r= 0.26). In summary, we identified several plasma proteins that were significantly associated with cognitive performance in older adults with obesity and metabolic syndrome, although further research is needed to replicate the results in larger samples and to include a predictive perspective.

Longitudinal association of dietary carbohydrate quality with visceral fat deposition and other adiposity indicators.

BACKGROUND & AIMS: The quality of dietary carbohydrates rather than total carbohydrate intake may determine the accumulation of visceral fat; however, to date, few studies have examined the impact of diet on adiposity using specific imaging techniques. Thus, the aim of this prospective study was to investigate the association between concurrent changes in carbohydrate quality index (CQI) and objectively-quantified adiposity distribution over a year. METHODS: We analyzed a cohort of 1476 participants aged 55-75 years with overweight/obesity and metabolic syndrome (MetS) from the PREDIMED-Plus randomized controlled trial. Dietary intake information was obtained at baseline, 6- and 12-months from a validated 143-item semi-quantitative food-frequency questionnaire, and CQI (range: 4 to 20) was calculated based on four dietary criteria: total dietary fibre, glycemic index, wholegrain/total grain carbohydrate ratio, and solid/total carbohydrate ratio. Overall and regional adiposity (total body fat, visceral fat and android-to-gynoid fat ratio) was quantified using dual-energy X-ray absorptiometry at all three time points. Multiple adjusted linear mixed-effects models were used to assess associations between concurrent changes in repeatedly measured CQI and adiposity over time. RESULTS: After controlling for potential confounding factors, a 3-point increment in CQI over 12-month follow-up was associated with a decrease in visceral fat (ß -0.067 z-score, 95% CI -0.088; -0.046, p < 0.001), android-to-gynoid fat ratio (-0.038, -0.059; -0.017, p < 0.001), and total fat (-0.064, -0.080; -0.047, p < 0.001). Fibre intake and the ratio of wholegrain/total grain showed the strongest inverse associations with all adiposity indicators. CONCLUSIONS: In this prospective cohort of older adults with overweight/obesity and MetS, we found that improvements in dietary carbohydrate quality over a year were associated with concurrent favorable changes in visceral and overall fat deposition. These associations were mostly driven by dietary fibre and the wholegrain/total grain ratio. TRIAL REGISTRATION: The trial was registered at the International Standard Randomized. CONTROLLED TRIAL: (ISRCTN: http://www.isrctn.com/ISRCTN89898870) with number 89898870 and registration date of 24 July 2014, retrospectively registered.

Nut consumption is associated with a shift of the NMR lipoprotein subfraction profile to a less atherogenic pattern among older individuals at high CVD risk.

BACKGROUND: Scientific evidence has accumulated on the beneficial effects of nut consumption on cardiovascular risk and cholesterol reduction, but few studies have examined the effects of nuts on advanced measures of lipoprotein atherogenicity determined by nuclear magnetic resonance (NMR) spectroscopy. We analyzed associations between the amount and type of of nuts consumed and advanced measures of lipoprotein atherogenity and insulin resistance in older individuals at high cardiovascular risk. METHODS: The present observational study was carried out within the framework of the Prevención con Dieta Mediterránea (PREDIMED) trial. Cross-sectional and longitudinal analyses after 1-year of follow-up were conducted in 196 men and women recruited in the PREDIMED-Reus (Spain) center. Dietary intake was assessed using a validated semi-quantitative food questionnaire. Baseline and 1-year fasting plasma lipoprotein and metabolite profiling were performed in plasma using NMR spectra Vantera® Clinical Analyzer. Associations by tertiles of nut consumption between baseline and 1-year changes and advanced measures of lipoprotein atherogenicity, branched chain amminoacids, and measures of insulin resistance were tested by multivariable-adjusted ANCOVA models. RESULTS: Compared to paticipants in the bottom tertile, those in the top tertile of total nut consumption showed higher levels of large HDL particles and HDL-cholesterol, lower levels of branched-chain amino acids (BCAA) and GlycA, and reduced lipoprotein insulin resistance and diabetes risk index. Participants in the top tertile of walnut consumption disclosed lower levels of very large VLDL, total LDL particles, LDL-cholesterol, and GlycA. Participants in the top tertile of non-walnut nut consumption displayed higher levels of total HDL particles, HDL-cholesterol and apoliporotein A1, lower BCAA and GlycA, and reduced lipoprotein insulin resistance. Participants in the top tertile of 1-year changes in walnut consumption showed increases in medium-sized HDL particles in comparison to the bottom tertile. CONCLUSIONS: In older individuals at high cardiovascular risk, increasing nut consumption was associated with a shift of the NMR lipoprotein subfraction profile to a less atherogenic pattern, as well as lower circulating concentrations of BCAA and decreased insulin resistance. These results provide novel mechanistic insight into the cardiovascular benefit of nut consumption. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003.

One-year longitudinal association between changes in dietary choline or betaine intake and cardiometabolic variables in the PREvención con DIeta MEDiterránea-Plus (PREDIMED-Plus) trial.

BACKGROUND: Choline and betaine intakes have been related to cardiovascular health. OBJECTIVES: We aimed to explore the relation between 1-y changes in dietary intake of choline or betaine and 1-y changes in cardiometabolic and renal function traits within the frame of the PREDIMED (PREvención con DIeta MEDiterránea)-Plus trial. METHODS: We used baseline and 1-y follow-up data from 5613 participants (48.2% female and 51.8% male; mean ± SD age: 65.01 ± 4.91 y) to assess cardiometabolic traits, and 3367 participants to assess renal function, of the Spanish PREDIMED-Plus trial. Participants met ≥3 criteria of metabolic syndrome and had overweight or obesity [BMI (in kg/m2) ≥27 and ≤40]. These criteria were similar to those of the PREDIMED parent study. Dietary intakes of choline and betaine were estimated from the FFQ. RESULTS: The greatest 1-y increase in dietary choline or betaine intake (quartile 4) was associated with improved serum glucose concentrations (-3.39 and -2.72 mg/dL for choline and betaine, respectively) and HbA1c levels (-0.10% for quartile 4 of either choline or betaine intake increase). Other significant changes associated with the greatest increase in choline or betaine intake were reduced body weight (-2.93 and -2.78 kg, respectively), BMI (-1.05 and -0.99, respectively), waist circumference (-3.37 and -3.26 cm, respectively), total cholesterol (-4.74 and -4.52 mg/dL, respectively), and LDL cholesterol (-4.30 and -4.16 mg/dL, respectively). Urine creatinine was reduced in quartile 4 of 1-y increase in choline or betaine intake (-5.42 and -5.74 mg/dL, respectively). CONCLUSIONS: Increases in dietary choline or betaine intakes were longitudinally related to improvements in cardiometabolic parameters. Markers of renal function were also slightly improved, and they require further investigation.This trial was registered at https://www.isrctn.com/ as ISRCTN89898870.

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.

Pro-vegetarian food patterns and cardiometabolic risk in the PREDIMED-Plus study: a cross-sectional baseline analysis.

PURPOSE: We explored the cross-sectional association between the adherence to three different provegetarian (PVG) food patterns defined as general (gPVG), healthful (hPVG) and unhealthful (uPVG), and the cardiometabolic risk in adults with metabolic syndrome (MetS) of the PREDIMED-Plus randomized intervention study. METHODS: We performed a cross-sectional analysis of baseline data from 6439 participants of the PREDIMED-Plus randomized intervention study. The gPVG food pattern was built by positively scoring plant foods (vegetables/fruits/legumes/grains/potatoes/nuts/olive oil) and negatively scoring, animal foods (meat and meat products/animal fats/eggs/fish and seafood/dairy products). The hPVG and uPVG were generated from the gPVG by adding four new food groups (tea and coffee/fruit juices/sugar-sweetened beverages/sweets and desserts), splitting grains and potatoes and scoring them differently. Multivariable-adjusted robust linear regression using MM-type estimator was used to assess the association between PVG food patterns and the standardized Metabolic Syndrome score (MetS z-score), a composed index that has been previously used to ascertain the cardiometabolic risk, adjusting for potential confounders. RESULTS: A higher adherence to the gPVG and hPVG was associated with lower cardiometabolic risk in multivariable models. The regression coefficients for 5th vs. 1st quintile were - 0.16 (95% CI: - 0.33 to 0.01) for gPVG (p trend: 0.015), and - 0.23 (95% CI: - 0.41 to - 0.05) for hPVG (p trend: 0.016). In contrast, a higher adherence to the uPVG was associated with higher cardiometabolic risk, 0.21 (95% CI: 0.04 to 0.38) (p trend: 0.019). CONCLUSION: Higher adherence to gPVG and hPVG food patterns was generally associated with lower cardiovascular risk, whereas higher adherence to uPVG was associated to higher cardiovascular risk.

Inflammatory potential of diet and bone mineral density in a senior Mediterranean population: a cross-sectional analysis of PREDIMED-Plus study.

PURPOSE: Inflammation could play a key role in tissue damage and bone metabolism. The modified dietary inflammatory score (M-DIS) is a validated tool to estimate the inflammatory potential of the diet. In the present study, we evaluate the associations between the M-DIS and bone mineral density (BMD) in a senior Mediterranean population with overweight/obesity and metabolic syndrome. METHODS: Baseline cross-sectional association between the M-DIS and bone mineral density was assessed in 1134 participants of the multicenter PREDIMED-Plus trial (aged 55-75 with overweight/obesity and metabolic syndrome). BMD was measured using Dual-energy X-ray Absorptiometry scans and participants answered a food frequency questionnaire to determine the M-DIS. BMD was categorized as low BMD when T score was equal or lower than -1 and normal BMD in another case. Associations between BMD and M-DIS were evaluated by using linear and logistic regressions adjusted by other co-variates. RESULTS: Participants in the top tertile of the M-DIS had a lower BMD at total femur [ß (95% CI) - 0.02 (- 0.04, - 0.01)], trochanter areas [ß (95% CI) - 0.03 (- 0.05, - 0.01)] and lumbar spine area [ß (95% CI) - 0.03 (- 0.07, 0.01)] (but in the last case, measures were less precise and hence not statistically significant) compared to those in the lower M-DIS tertile. Multiple logistic regression analyses showed that the odds of the total femur and femoral trochanter osteopenia/osteoporosis were higher in participants in the top tertile compared to those in the lowest tertile of M-DIS [OR (95% CI) 1.71 (1.12, 2.64), P for trend 0.015; 2.02 (1.29, 3.21), P for trend 0.002, respectively]. CONCLUSION: A high pro-inflammatory diet, measured by the M-DIS, is associated with lower BMD in a senior Mediterranean population with metabolic syndrome.

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 .

Impact of COVID-19 pandemic on the PREDIMED-Plus randomized clinical trial: Effects on the interventions, participants follow-up, and adiposity.

Background: The COVID-19 pandemic has affected the implementation of most ongoing clinical trials worldwide including the PREDIMED-Plus study. The PREDIMED-Plus is an ongoing, multicenter, controlled intervention trial, aimed at weight-loss and cardiovascular disease prevention, in which participants were randomized (1:1 ratio) to an intervention group (energy-reduced Mediterranean diet, promotion of physical activity, and behavioral support) or to a control group (Mediterranean diet with usual care advice). When the pandemic began, the trial was in the midst of the planned intervention. The objective of this report was to examine the effects of the pandemic on the delivery of the intervention and to describe the strategies established to mitigate the possible adverse effects of the pandemic lockdown on data collection and adiposity. Methods: We assessed the integrity of the PREDIMED-Plus trial during 5 identified periods of the COVID-19 pandemic determined according to restrictions dictated by the Spanish government authorities. A standardized questionnaire was delivered to each of the 23 PREDIMED-Plus recruiting centers to collected data regarding the trial integrity. The effect of the restrictions on intervention components (diet, physical activity) was evaluated with data obtained in the three identified lockdown phases: pre lockdown, lockdown proper, and post lockdown. Results: During the lockdown (March/2020-June/2021), 4,612 participants (48% women, mean age 65y) attended pre-specified yearly follow-up visits to receive lifestyle recommendations and obtain adiposity measures. The overall mean (SD) of the proportions reported by each center showed that 40.4% (25.4) participants had in-person visits, 39.8% (18.2) participants were contacted by telephone and 35% (26.3) by electronic means. Participants' follow-up and data collection rates increased across lockdown periods (from ≈10% at onset to ≈80% at the end). Compared to pre-lockdown, waist circumference increased during (0.75 cm [95% CI: 0.60-0.91]) and after (0.72 cm [95% CI: 0.56-0.89]) lockdown. Body weight did not change during lockdown (0.01 kg [95% CI: -0.10 to 0.13) and decreased after lockdown (-0.17 kg [95% CI: -0.30 to -0.04]). Conclusion: Mitigating strategies to enforce the intervention and patient's follow-up during lockdown have been successful in preserving the integrity of the trial and ensuring its continuation, with minor effects on adiposity. Clinical trial registration: https://doi.org/10.1186/ISRCTN89898870, identifier ISRCTN89898870.

Interplay between cognition and weight reduction in individuals following a Mediterranean Diet: Three-year follow-up of the PREDIMED-Plus trial.

BACKGROUND & AIMS: Some cognitive profiles might facilitate successful weight loss and its maintenance. Also, weight reductions may result in cognitive benefits. However, little work to date has examined the interactions between cognition and weight changes in the context of interventions with the Mediterranean diet (MedDiet). We studied the within-subject longitudinal relationships between cognition, body mass index (BMI), physical activity (PA), and quality of life (QoL), in older adults following a MedDiet. METHODS: The PREDIMED-Plus is a primary prevention trial testing the effect of a lifestyle intervention program with an energy-restricted MedDiet (er-MedDiet), weight-loss goals and PA promotion on cardiovascular disease. The PREDIMED-Plus-Cognition sub-study included 487 participants (50% women, mean age 65.2 ± 4.7 years), with overweight/obesity, metabolic syndrome and normal cognitive performance at baseline. A comprehensive neurocognitive test battery was administered at baseline and after 1 and 3 years. RESULTS: Baseline higher performance in verbal memory (OR = 1.5; 95%CI 1.0, 2.1), visuoconstructive praxis and attention (OR = 1.5; 95%CI 0.9, 2.3), and inhibition (OR = 1.3; 95%CI 0.9, 1.9) were associated with a higher odd of achieving at least 8% weight loss after 3 years follow-up in participants randomized to the intervention group. There were moderate improvements in specific tests of memory and executive functions during follow-up. Higher adherence to the er-MedDiet was associated with greater improvements in memory. Women exhibited lower rates of change in global cognition, PA and QoL. Moreover, improvements in memory correlated with reductions in BMI after 1 year (ßSTD = -0.14) and with improvements in PA after 3 years (ßSTD = 0.13). Finally, participants who experienced greater improvements in executive functions and global cognition also experienced greater improvements in their QoL. CONCLUSIONS: This study refines the understanding of the determinants and mutual interrelationships between longitudinally-assessed cognitive performance and weight loss, adding further evidence to the cognitive benefits associated with better adherence to a MedDiet. Our results also suggest that weight loss interventions tailored to the cognitive profile and gender of participants are promising avenues for future studies.

Dairy products intake and the risk of incident cataracts surgery in an elderly Mediterranean population: results from the PREDIMED study.

PROPOSAL: The aim of this study was to examine the association between the consumption of total and specific types of dairy products and the risk of incident cataracts in an elderly Mediterranean population at high cardiovascular risk. METHODS: We prospectively analyzed 5860 subjects from the PREvención con DIeta MEDiterránea (PREDIMED) Study. The time to cataract surgery was calculated as the time between recruitment and the date of the surgery, last visit of the follow-up, date of death, or until the end of the study. Dairy products intake was assessed using validated food frequency questionnaires. We used Cox proportional hazard regression to assess the risk of cataract surgery according to average dietary energy-adjusted total dairy products, milk, yogurt and cheese consumption. RESULTS: We documented a total of 768 new cataract events after a median of 5.6 years of follow-up. Subjects in the second [hazard ratio (HR) 0.62; 95% CI 0.52, 0.74] and third tertile (HR: 0.71; 95% CI 0.60, 0.85) of skimmed yogurt intake had a significantly lower risk of cataracts after adjusting for potential confounders. No significant associations were observed for total dairy products, whole and skimmed milk, whole yogurt and cheese consumption. CONCLUSION: The intake of skimmed yogurt was associated with a reduced risk of cataracts in an elderly Mediterranean population with high cardiovascular risk. No significant associations were observed for other type of dairy product. CLINICAL TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.

Association of Dietary Vitamin K1 Intake With the Incidence of Cataract Surgery in an Adult Mediterranean Population: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Cataract, one of the most frequent causes of blindness in developed countries, is strongly associated with aging. The exact mechanisms underlying cataract formation are still unclear, but growing evidence suggests a potential role of inflammatory and oxidative processes. Therefore, antioxidant and anti-inflammatory factors of the diet, such as vitamin K1, could play a protective role. Objective: To examine the association between dietary vitamin K1 intake and the risk of incident cataracts in an elderly Mediterranean population. Design, Setting, and Participants: A prospective analysis was conducted in 5860 participants from the Prevención con Dieta Mediterránea Study, a randomized clinical trial executed between 2003 and 2011. Participants were community-dwelling men (44.2%) and women (55.8%), and the mean (SD) age was 66.3 (6.1) years. Main Outcomes and Measures: Dietary vitamin K1 intake was evaluated using a validated food frequency questionnaire. The time to the cataract event was calculated as the time between recruitment and the date of the occurrence to cataract surgery, the time to the last visit of the follow-up, date of death, or the end of the study. Hazard ratios and 95% CIs for cataract incidence were estimated with a multivariable Cox proportional hazards model. Results: Participants were community-dwelling men (44.2%; n = 868) and women (55.8%; n = 1086), and the mean (SD) age was 66.3 (6.1) years. After a median of 5.6 years follow-up, we documented a total of 768 new cataracts. Participants in the highest tertile of dietary vitamin K1 intake had a lower risk of cataracts than those in the lowest tertile (hazard ratio, 0.71; 95% CI, 0.58-0.88; P = .002), after adjusting for potential confounders. Conclusions and Relevance: High intake of dietary vitamin K1 was associated with a reduced risk of cataracts in an elderly Mediterranean population even after adjusting by other potential confounders. Trial Registration: isrctn.org: ISRCTN35739639.