Publications by authors named "Aleix Sala-Vila"

83 Publications

Effects of Walnut Consumption for 2 Years on Lipoprotein Subclasses Among Healthy Elders: Findings From the WAHA Randomized Controlled Trial.

Circulation 2021 Aug 30. Epub 2021 Aug 30.

Lipid Clinic, Endocrinology and Nutrition Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Spain.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054051DOI Listing
August 2021

The 3-Year Effect of the Mediterranean Diet Intervention on Inflammatory Biomarkers Related to Cardiovascular Disease.

Biomedicines 2021 Jul 22;9(8). Epub 2021 Jul 22.

Department of Internal Medicine, Hospital Clinic de Barcelona, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.

The intervention with the Mediterranean diet (MD) pattern has evidenced short-term anti-inflammatory effects, but little is known about its long-term anti-inflammatory properties at molecular level. This study aims to investigate the 3-year effect of MD interventions compared to low-fat diet (LFD) on changes on inflammatory biomarkers related to atherosclerosis in a free-living population with a high-risk of cardiovascular disease (CD). Participants ( = 285) in the PREDIMED trial were randomly assigned into three intervention groups: MD with extra-virgin olive oil (EVOO) or MD-Nuts, and a LFD. Fourteen plasma inflammatory biomarkers were determined by Luminex assays. An additional pilot study of gene expression (GE) was determined by RT-PCR in 35 participants. After 3 years, both MDs showed a significant reduction in the plasma levels of IL-1β, IL-6, IL-8, TNF-α, IFN-γ, hs-CRP, MCP-1, MIP-1β, RANTES, and ENA78 ( < 0.05; all). The decreased levels of IL-1β, IL-6, IL-8, and TNF-α after MD significantly differed from those in the LFD ( < 0.05). No significant changes were observed at the gene level after MD interventions, however, the GE of CXCR2 and CXCR3 tended to increase in the control LFD group ( = 0.09). This study supports the implementation of MD as a healthy long-term dietary pattern in the prevention of CD in populations at high cardiovascular risk.
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http://dx.doi.org/10.3390/biomedicines9080862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389558PMC
July 2021

Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile.

Alzheimers Res Ther 2021 07 27;13(1):134. Epub 2021 Jul 27.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain.

Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile.

Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F]-FDG, and [F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex.

Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2.

Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials.

Trial Registration: NCT02485730.
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http://dx.doi.org/10.1186/s13195-021-00863-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314554PMC
July 2021

Walnuts, Long-Chain Polyunsaturated Fatty Acids, and Adolescent Brain Development: Protocol for the Walnuts Smart Snack Dietary Intervention Trial.

Front Pediatr 2021 8;9:593847. Epub 2021 Jun 8.

ISGlobal- Instituto de Salud Global de Barcelona-Campus MAR, Parc de Recerca Biomèdica de Barcelona (PRBB), Barcelona, Spain.

Adolescence, when the most complex behaviors are refined to adult sophistication, represents a major window of opportunity and vulnerability for neuropsychological development. To support and protect this complex and active brain growth, different nutritional components considered essential need to be acquired from the diet. For instance, omega-3 fatty acids are mainly obtained from seafood, seeds, and walnuts. Known for their rich lipid profile, walnuts contain sizable amounts of an essential fatty acid, alpha-linolenic acid (ALA), the vegetable omega-3 fatty acid that is the precursor of two longer-chain omega-3 polyunsaturated fatty acids (omega-3 PUFA): docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. While there is growing evidence of neuropsychological improvements in the young developing brain associated with omega-3 PUFA intake, few studies have examined whether consuming walnuts during adolescence entails similar beneficial effects. There is a need to further explore the ways in which walnuts influence youthful brain function, particularly for the long-term. Thus, we designed the WALNUTs study (WSS), a population-based randomized controlled trial conducted in adolescents in Barcelona, Spain. We hypothesize that walnut intake will increase omega-3 PUFA tissue availability (particularly ALA) to a level that enhances the neuropsychological development during adolescence. We conducted a 6-month population-based randomized controlled trial in teenagers ( = 800) and we aimed to determine the effectiveness of the intervention (four walnuts per day, or 30 kernel g, ~1.5g of ALA) in enhancing brain neuropsychological and socio-emotional development compared to a control group with no walnut intervention. Before randomization, different neuropsychological tests were recorded for all participants, and blood samples (in a subsample of participants) were collected to measure omega-3 PUFA levels at baseline, and all again, after randomization and the intervention. The data is now collected and we will conduct linear regression models to assess the effect of the intervention. The WALNUTs (WSS) study results will allow us to better understand the role of plant-based omega-3 PUFA intake from regular walnut consumption on neuropsychological development during adolescence. Results could be translated into nutritional public health recommendations targeting teenagers. ClinicalTrials.gov, U.S. National Library of Medicine, National Institutes of Health # NCT02590848. Retrospectively registered 29/10/2015.
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http://dx.doi.org/10.3389/fped.2021.593847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217431PMC
June 2021

Biomarkers of fatty acid intake are independently associated with preclinical atherosclerosis in individuals with type 1 diabetes.

Eur J Nutr 2021 Jun 18. Epub 2021 Jun 18.

Endocrinology and Nutrition Department, Hospital Clinic de Barcelona, Carrer de Villarroel, 170, 08036, Barcelona, Spain.

Purpose: Information on the association between diet and cardiovascular disease (CVD) in type 1 diabetes (T1D) is scarce. We assessed the association between biomarkers of fatty acid (FA) intake and the presence of carotid plaques (a surrogate marker of future CVD events) in this high-risk population.

Methods: Cross-sectional study in 167 consecutive T1D patients without CVD and with at least one of the following: ≥ 40 years, diabetic nephropathy, or ≥ 10 years of T1D duration with another CVD risk factor. The FA profile of erythrocyte membranes was determined by gas chromatography, and the number of carotid plaques (intima-media thickness ≥ 1.5 mm) was assessed by ultrasonography. Regression models were constructed adjusting for classical (age, gender, blood pressure, smoking habit, LDL-cholesterol, body mass index and statins) and T1D-specific risk factors (diabetes duration, HbA1c and chronic complications).

Results: A total of 58.7% were men (mean age 48.3 ± 10.3 years, T1D duration 27.2 ± 10.1 years). Sixty-one patients (36.5%) showed carotid plaque. Linoleic acid decreased and all-C18:1trans increased with the number of carotid plaques (none, 1-2, ≥ 3 plaques; p for trend < 0.05). In multivariate regression models, linoleic acid remained inversely associated with the presence of plaque [1% increase of total FAs; OR 0.71 (0.53-0.95), p = 0.021] and ≥ 2 plaques [OR 0.70 (0.51-0.98), p = 0.039]; whereas, all-C18:1trans was positively associated with ≥ 3 plaques (0.1% increase of total FAs; OR 1.51 [1.05-2.16], p = 0.026).

Conclusions: Erythrocyte FA composition, as a biomarker of FA intake, was independently associated with preclinical atherosclerosis in T1DM. Our data support the potential role of an unfavorable pattern of fat intake and CVD risk in this population.
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http://dx.doi.org/10.1007/s00394-021-02611-2DOI Listing
June 2021

Using an erythrocyte fatty acid fingerprint to predict risk of all-cause mortality: the Framingham Offspring Cohort.

Am J Clin Nutr 2021 Jun 16. Epub 2021 Jun 16.

The Fatty Acid Research Institute, Sioux Falls, SD, USA.

Background: RBC long-chain omega-3 (n-3) fatty acid (FA) percentages (of total fatty acids) are associated with lower risk for total mortality, but it is unknown if a suite of FAs could improve risk prediction.

Objectives: The objective of this study was to compare a combination of RBC FA levels with standard risk factors for cardiovascular disease (CVD) in predicting risk of all-cause mortality.

Methods: Framingham Offspring Cohort participants without prevalent CVD having RBC FA measurements and relevant baseline clinical covariates (n = 2240) were evaluated during 11 y of follow-up. A forward, stepwise approach was used to systematically evaluate the association of 8 standard risk factors (age, sex, total cholesterol, HDL cholesterol, hypertension treatment, systolic blood pressure, smoking status, and prevalent diabetes) and 28 FA metrics with all-cause mortality. A 10-fold cross-validation process was used to build and validate models adjusted for age and sex.

Results: Four of 28 FA metrics [14:0, 16:1n-7, 22:0, and omega-3 index (O3I; 20:5n-3 + 22:6n-3)] appeared in ≥5 of the discovery models as significant predictors of all-cause mortality. In age- and sex-adjusted models, a model with 4 FA metrics was at least as good at predicting all-cause mortality as a model including the remaining 6 standard risk factors (C-statistic: 0.778; 95% CI: 0.759, 0.797; compared with C-statistic: 0.777; 95% CI: 0.753, 0.802). A model with 4 FA metrics plus smoking and diabetes (FA + Sm + D) had a higher C-statistic (0.790; 95% CI: 0.770, 0.811) compared with the FA (P < 0.01) or Sm + D models alone (C-statistic: 0.766; 95% CI: 0.739, 0.794; P < 0.001). A variety of other highly correlated FAs could be substituted for 14:0, 16:1n-7, 22:0, or O3I with similar predicted outcomes.

Conclusions: In this community-based population in their mid-60s, RBC FA patterns were as predictive of risk for death during the next 11 y as standard risk factors. Replication is needed in other cohorts to validate this FA fingerprint as a predictor of all-cause mortality.
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http://dx.doi.org/10.1093/ajcn/nqab195DOI Listing
June 2021

Amyloid-β positive individuals with subjective cognitive decline present increased CSF neurofilament light levels that relate to lower hippocampal volume.

Neurobiol Aging 2021 08 6;104:24-31. Epub 2021 Mar 6.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; Present address: H. Lundbeck A/S, Denmark. Electronic address:

Neurofilament light chain (NfL) is an axonal protein that when measured in cerebrospinal fluid (CSF) serves as a biomarker of neurodegeneration. We aimed at investigating the association among CSF NfL, presence of Subjective Cognitive Decline (SCD) and hippocampal volume, and how CSF amyloid-β (Aβ) modifies these associations. We included 278 cognitively unimpaired participants from the Alfa+ cohort (78 SCD and 200 Controls). Linear models accounting for covariates (age, gender, and mood) were used to test the association between CSF NfL and SCD status, and between CSF NfL and bilateral hippocampal volumes. Interactions with Aβ were also explored. Individuals with SCD had higher CSF NfL and lower CSF Aβ42/40 than Controls. There was a significant interaction between SCD and CSF-Aβ42/40 levels. Stratified analyses showed a significant association between SCD and NfL only in Aβ+ individuals. Higher CSF NfL was significantly associated with lower hippocampal volume specifically in Aβ+ individuals with SCD. The presence of SCD in Aβ+ individuals may represent an early symptom in the Alzheimer's continuum related to incipient neurodegeneration.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.026DOI Listing
August 2021

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

Nat Commun 2021 04 22;12(1):2329. Epub 2021 Apr 22.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.
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http://dx.doi.org/10.1038/s41467-021-22370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062567PMC
April 2021

DHA intake relates to better cerebrovascular and neurodegeneration neuroimaging phenotypes in middle-aged adults at increased genetic risk of Alzheimer disease.

Am J Clin Nutr 2021 06;113(6):1627-1635

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: The number of APOE-ε4 alleles is a major nonmodifiable risk factor for sporadic Alzheimer disease (AD). There is increasing evidence on the benefits of dietary DHA (22:6n-3) before the onset of AD symptoms, particularly in APOE-ε4 carriers. Brain alterations in the preclinical stage can be detected by structural MRI.

Objectives: We aimed, in middle-aged cognitively unimpaired individuals at increased risk of AD, to cross-sectionally investigate whether dietary DHA intake relates to cognitive performance and to MRI-based markers of cerebral small vessel disease and AD-related neurodegeneration, exploring the effect modification by APOE-ε4 status.

Methods: In 340 participants of the ALFA (ALzheimer and FAmilies) study, which is enriched for APOE-ε4 carriership (n = 122, noncarriers; n = 157, 1 allele; n = 61, 2 alleles), we assessed self-reported DHA intake through an FFQ. We measured cognitive performance by administering episodic memory and executive function tests. We performed high-resolution structural MRI to assess cerebral small vessel disease [white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs)] and AD-related brain atrophy (cortical thickness in an AD signature). We constructed regression models adjusted for potential confounders, exploring the interaction DHA × APOE-ε4.

Results: We observed no significant associations between DHA and cognitive performance or WMH burden. We observed a nonsignificant inverse association between DHA and prevalence of lobar CMBs (OR: 0.446; 95% CI: 0.195, 1.018; P = 0.055). DHA was found to be significantly related to greater cortical thickness in the AD signature in homozygotes but not in nonhomozygotes (P-interaction = 0.045). The association strengthened when analyzing homozygotes and nonhomozygotes matched for risk factors.

Conclusions: In cognitively unimpaired APOE-ε4 homozygotes, dietary DHA intake related to structural patterns that may result in greater resilience to AD pathology. This is consistent with the current hypothesis that those subjects at highest risk would obtain the largest benefits from DHA supplementation in the preclinical stage.This trial was registered at clinicaltrials.gov as NCT01835717.
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http://dx.doi.org/10.1093/ajcn/nqab016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168359PMC
June 2021

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease.

Alzheimers Res Ther 2021 02 17;13(1):46. Epub 2021 Feb 17.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Recognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.

Methods: This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.

Results: Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = - 0.141, p = 0.005), t-tau (β = - 0.147 p = 0.004) and neurogranin levels (β = - 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.

Conclusions: Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.

Trial Registration: NCT01835717 , NCT02485730 , NCT02685969 .
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http://dx.doi.org/10.1186/s13195-021-00781-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890889PMC
February 2021

Ellagic Acid as a Tool to Limit the Diabetes Burden: Updated Evidence.

Antioxidants (Basel) 2020 Dec 3;9(12). Epub 2020 Dec 3.

IMIM-Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain.

Oxidative stress contributes not only to the pathogenesis of type 2 diabetes (T2D) but also to diabetic vascular complications. It follows that antioxidants might contribute to limiting the diabetes burden. In this review we focus on ellagic acid (EA), a compound that can be obtained upon intestinal hydrolysis of dietary ellagitannins, a family of polyphenols naturally found in several fruits and seeds. There is increasing research on cardiometabolic effects of ellagitannins, EA, and urolithins (EA metabolites). We updated research conducted on these compounds and (I) glucose metabolism; (II) inflammation, oxidation, and glycation; and (III) diabetic complications. We included studies testing EA in isolation, extracts or preparations enriched in EA, or EA-rich foods (mostly pomegranate juice). Animal research on the topic, entirely conducted in murine models, mostly reported glucose-lowering, antioxidant, anti-inflammatory, and anti-glycation effects, along with prevention of micro- and macrovascular diabetic complications. Clinical research is incipient and mostly involved non-randomized and low-powered studies, which confirmed the antioxidant and anti-inflammatory properties of EA-rich foods, but without conclusive results on glucose control. Overall, EA-related compounds might be potential agents to limit the diabetes burden, but well-designed human randomized controlled trials are needed to fill the existing gap between experimental and clinical research.
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http://dx.doi.org/10.3390/antiox9121226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761821PMC
December 2020

Linoleic Acid Status in Cell Membranes Inversely Relates to the Prevalence of Symptomatic Carotid Artery Disease.

Stroke 2021 Jan 4;52(2):703-706. Epub 2020 Dec 4.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain (M.C., E.O., T.-M.F.-S., L.L.L., S.A., A.S.-V.).

Background And Purpose: The red blood cell fatty acid composition objectively reflects the long-term dietary intake of several fatty acids. In patients undergoing carotid endarterectomy, we explored whether red blood cell status of selected fatty acids related to symptomatic carotid artery disease.

Methods: We included patients with symptomatic (n=22) and asymptomatic (n=23) carotid artery disease. We determined all-C18:1 trans, linoleic acid (LA, C18:2n6), alpha-linolenic acid (C18:3n3), and the omega-3 index (sum of eicosapentaenoic [C20:5n3] and docosahexaenoic [C22:6n3] acids) in both red blood cells and carotid plaque phospholipids by gas-chromatography.

Results: In a multivariate logistic regression analysis, we only observed a significant association for LA, whose red blood cell status was inversely related to symptomatic carotid artery disease (odds ratio, 0.116 [95% CI, 0.022-0.607], =0.011, for each 1-SD increase). A similar result was observed for LA in carotid plaque phospholipids.

Conclusions: Cell membrane enrichment in LA, which reflects its intake, was inversely related to symptomatic carotid disease. This increases evidence supporting a favorable role of dietary LA in vascular health.
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http://dx.doi.org/10.1161/STROKEAHA.120.030477DOI Listing
January 2021

Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected.

EMBO Mol Med 2020 12 10;12(12):e12921. Epub 2020 Nov 10.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

In Alzheimer's disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p-tau) in the preclinical stage of the Alzheimer's continuum. We measured three novel CSF p-tau biomarkers, phosphorylated at threonine-181 and threonine-217 with an N-terminal partner antibody and at threonine-231 with a mid-region partner antibody. These were compared with an automated mid-region p-tau181 assay (Elecsys) as the gold standard p-tau measure. We demonstrate that these novel p-tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid-β (Aβ) pathology are detected, and can accurately differentiate Aβ-positive from Aβ-negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N-terminal p-tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p-tau assays.
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http://dx.doi.org/10.15252/emmm.202012921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721364PMC
December 2020

Circulating Omega-3 Fatty Acids and Incident Adverse Events in Patients With Acute Myocardial Infarction.

J Am Coll Cardiol 2020 11;76(18):2089-2097

Department of Cardiology, Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona (Barcelona), Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Background: Dietary omega-3 eicosapentaenoic acid (EPA) has multiple cardioprotective properties. The proportion of EPA in serum phosphatidylcholine (PC) mirrors dietary EPA intake during previous weeks. Circulating EPA in ST-segment elevation myocardial infarction (STEMI) relates to smaller infarct size and preserved long-term ventricular function.

Objectives: The authors investigated whether serum-PC EPA (proxy for marine omega-3 consumption) levels at the time of STEMI were associated with a lower incidence of major adverse cardiovascular events (MACE), all-cause mortality, and readmission for cardiovascular (CV) causes at 3 years' follow-up. We also explored the association of alpha-linolenic acid (ALA, proxy for vegetable omega-3 intake) with all-cause mortality and MACE.

Methods: The authors prospectively included 944 consecutive patients with STEMI (mean age 61 years, 209 women) undergoing primary percutaneous coronary intervention. We determined serum-PC fatty acids with gas chromatography.

Results: During follow-up, 211 patients had MACE, 108 died, and 130 were readmitted for CV causes. A Cox proportional hazards model adjusted for known clinical predictors showed that serum-PC EPA at the time of STEMI was inversely associated with both incident MACE and CV readmission (hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.62 to 0.94, and HR: 0.74; 95% CI: 0.58 to 0.95, respectively, for a 1-standard deviation [SD] increase). Serum-PC ALA was inversely related to all-cause mortality (HR: 0.65; 95% CI: 0.44 to 0.96, for a 1-SD increase).

Conclusions: Elevated serum-PC EPA and ALA levels at the time of STEMI were associated with a lower risk of clinical adverse events. Consumption of foods rich in these fatty acids might improve the prognosis of STEMI.
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http://dx.doi.org/10.1016/j.jacc.2020.08.073DOI Listing
November 2020

Effects of a Low Dose of Caffeine Alone or as Part of a Green Coffee Extract, in a Rat Dietary Model of Lean Non-Alcoholic Fatty Liver Disease without Inflammation.

Nutrients 2020 Oct 23;12(11). Epub 2020 Oct 23.

Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Avda Joan XXIII 27-31, 08028 Barcelona, Spain.

Non-alcoholic fatty liver disease is a highly prevalent condition without specific pharmacological treatment, characterized in the initial stages by hepatic steatosis. It was suggested that lipid infiltration in the liver might be reduced by caffeine through anti-inflammatory, antioxidative, and fatty acid metabolism-related mechanisms. We investigated the effects of caffeine (CAF) and green coffee extract (GCE) on hepatic lipids in lean female rats with steatosis. For three months, female Sprague-Dawley rats were fed a standard diet or a cocoa butter-based high-fat diet plus 10% liquid fructose. In the last month, the high-fat diet was supplemented or not with CAF or a GCE, providing 5 mg/kg of CAF. Plasma lipid levels and the hepatic expression of molecules involved in lipid metabolism were determined. Lipidomic analysis was performed in liver samples. The diet caused hepatic steatosis without obesity, inflammation, endoplasmic reticulum stress, or hepatic insulin resistance. Neither CAF nor GCE alleviated hepatic steatosis, but GCE-treated rats showed lower hepatic triglyceride levels compared to the CAF group. The GCE effects could be related to reductions of hepatic (i) mTOR phosphorylation, leading to higher nuclear lipin-1 levels and limiting lipogenic gene expression; (ii) diacylglycerol levels; (iii) hexosylceramide/ceramide ratios; and (iv) very-low-density lipoprotein receptor expression. In conclusion, a low dose of CAF did not reduce hepatic steatosis in lean female rats, but the same dose provided as a green coffee extract led to lower liver triglyceride levels.
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http://dx.doi.org/10.3390/nu12113240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690747PMC
October 2020

Leptin alters energy intake and fat mass but not energy expenditure in lean subjects.

Nat Commun 2020 10 13;11(1):5145. Epub 2020 Oct 13.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

Based on studies in mice, leptin was expected to decrease body weight in obese individuals. However, the majority of the obese are hyperleptinemic and do not respond to leptin treatment, suggesting the presence of leptin tolerance and questioning the role of leptin as regulator of energy balance in humans. We thus performed detailed novel measurements and analyses of samples and data from our clinical trials biobank to investigate leptin effects on mechanisms of weight regulation in lean normo- and mildly hypo-leptinemic individuals without genetic disorders. We demonstrate that short-term leptin administration alters food intake during refeeding after fasting, whereas long-term leptin treatment reduces fat mass and body weight, and transiently alters circulating free fatty acids in lean mildly hypoleptinemic individuals. Leptin levels before treatment initiation and leptin dose do not predict the observed weight loss in lean individuals suggesting a saturable effect of leptin. In contrast to data from animal studies, leptin treatment does not affect energy expenditure, lipid utilization, SNS activity, heart rate, blood pressure or lean body mass.
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http://dx.doi.org/10.1038/s41467-020-18885-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553922PMC
October 2020

One-year dietary supplementation with walnuts modifies exosomal miRNA in elderly subjects.

Eur J Nutr 2021 Jun 26;60(4):1999-2011. Epub 2020 Sep 26.

Laboratory of Epigenetics of Lipid Metabolism, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, IMDEA Food Institute, CEI UAM+CSIC, Ctra. De Cantoblanco 8, 28049, Madrid, Spain.

Purpose: Epidemiological studies and clinical trials support the association of nut consumption with a lower risk of prevalent non-communicable diseases, particularly cardiovascular disease. However, the molecular mechanisms underlying nut benefits remain to be fully described. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and play a pivotal role in health and disease. Exosomes are extracellular vesicles released from cells and mediate intercellular communication. Whether nut consumption modulates circulating miRNAs (c-miRNAs) transported in exosomes is poorly described.

Methods: Cognitively healthy elderly subjects were randomized to either control (n = 110, abstaining from walnuts) or daily supplementation with walnuts (15% of their total energy, ≈30-60 g/day, n = 101) for 1-year. C-miRNAs were screened in exosomes isolated from 10 samples, before and after supplementation, and identified c-miRNA candidates were validated in the whole cohort. In addition, nanoparticle tracking analysis and lipidomics were assessed in pooled exosomes from the whole cohort.

Results: Exosomal hsa-miR-32-5p and hsa-miR-29b-3p were consistently induced by walnut consumption. No major changes in exosomal lipids, nanoparticle concentration or size were found.

Conclusion: Our results provide novel evidence that certain c-miRNAs transported in exosomes are modulated by walnut consumption. The extent to which this finding contributes to the benefits of walnuts deserves further research.
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http://dx.doi.org/10.1007/s00394-020-02390-2DOI Listing
June 2021

Association of years to parent's sporadic onset and risk factors with neural integrity and Alzheimer biomarkers.

Neurology 2020 10 31;95(15):e2065-e2074. Epub 2020 Jul 31.

From the Barcelonaβeta Brain Research Center (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Pasqual Maragall Foundation; IMIM (Hospital del Mar Medical Research Institute) (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., A.S.-V, C.F., M.S.-C., J.D.G., J.L.M.), Barcelona; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (E.M.A.-U., G.S., G.O., C.M., G.S.-B., M.C.-B., O.G.-R., M.S.-C., J.L.M.), Madrid, Spain; Department of Epidemiology (M.C.-B.), Harvard TH Chan School of Public Health, Boston, MA; Servei de Neurologia (O.G.-R., M.S.-C.), Hospital del Mar, Barcelona; Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (C.F., J.D.G.), Madrid, Spain; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Mölndal; Department of Psychiatry and Neurochemistry (H.Z., K.B.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (H.Z.), London; and Universitat Pompeu Fabra (J.D.G., J.L.M.), Barcelona, Spain.

Objective: To evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic Alzheimer disease (AD) is associated with greater AD and neural injury biomarker alterations during midlife and to assess the role of nonmodifiable and modifiable factors.

Methods: This observational study included 290 cognitively unimpaired (CU) participants with a family history (FH) of clinically diagnosed sporadic AD (age 49-73 years) from the Alzheimer's and Families (ALFA) study. [F]flutemetamol-PET standardized uptake value ratios, CSF β-amyloid ratio, and phosphorylated tau were used as AD biomarkers. Hippocampal volumes and CSF total tau were used as neural injury biomarkers. Mental and vascular health proxies were calculated. In multiple regression models, we assessed the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. Then, we evaluated the effects of FH load (number of parents affected), sex, ε4, education, and vascular and mental health.

Results: Proximity to parental AAO was associated with β-amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing that women and older participants had increased β-amyloid. FH load and ε4 showed independent contributions to β-amyloid load. Education and vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age.

Conclusion: The identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for AD prevention. Proximity to parental AAO may offer a timeline for detection of incipient β-amyloid changes in women. In risk-enriched middle-aged cohorts, mental health may be a target for early interventions.

Clinicaltrialsgov Identifier: NCT02485730.

Classification Of Evidence: This study provides Class II evidence that in CU adults with FH of sporadic AD, proximity to parental AAO was associated with β-amyloid but not with neural injury biomarkers.
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http://dx.doi.org/10.1212/WNL.0000000000010527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774330PMC
October 2020

Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum.

Alzheimers Dement 2020 10 23;16(10):1358-1371. Epub 2020 Jun 23.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood.

Methods: We used NeuroToolKit and Elecsys immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum.

Results: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers.

Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.
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http://dx.doi.org/10.1002/alz.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586814PMC
October 2020

5--, - and Total Lycopene Plasma Concentrations Inversely Relate to Atherosclerotic Plaque Burden in Newly Diagnosed Type 2 Diabetes Subjects.

Nutrients 2020 Jun 6;12(6). Epub 2020 Jun 6.

Department of Endocrinology and Nutrition, August Pi i Sunyer Biomedical Research Institute-IDIBAPS, Hospital Clínic of Barcelona, 08036 Barcelona, Spain.

Diabetic subjects are at increased risk of cardiovascular disease. Atherosclerosis, the common soil of most of the cardiovascular complications, is more prevalent and extensive in this population due not only to hyperglycemia, insulin resistance, and dyslipidemia, but also to inflammation and oxidative stress. Lycopenes are bioactive compounds with antioxidant and anti-inflammatory activities mostly supplied by tomato and tomato byproducts. We investigated the association between circulating lycopenes and carotid plaque burden in diabetic patients, in a cross-sectional study in 105 newly diagnosed diabetic subjects. Atheroma plaque (wall thickness ≥ 1.5 mm), number of plaques, and plaque burden (sum of maximum heights of all plaques) were assessed by sonographic evaluation of carotid arteries. Plasma lycopenes (5--, 9--, 13--, and -lycopene) were quantified by high performance liquid chromatography-mass spectrometry HPLC-MS. Atheroma plaque was observed in 75 participants, from which 38 presented one plaque and 37 two or more carotid plaques. No differences were observed in the plasmatic concentrations of lycopenes between subjects with and without atherosclerotic plaque presence. However, plaque burden was inversely associated with 5--lycopene, all -lycopene isomers, -lycopene, and total lycopene isomers (all, < 0.05). High plasma levels of lycopenes inversely relate to atherosclerotic burden. We provide novel evidence that suggests that the consumption of compounds found in tomato and tomato byproducts might be beneficial for the prevention of atherosclerosis.
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http://dx.doi.org/10.3390/nu12061696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352372PMC
June 2020

Nutrition and the ageing brain: Moving towards clinical applications.

Ageing Res Rev 2020 09 24;62:101079. Epub 2020 May 24.

Department of Nutrition and Preventive Medicine, Norwich Medical School, University of East Anglia, Norwich, UK. Electronic address:

The global increases in life expectancy and population have resulted in a growing ageing population and with it a growing number of people living with age-related neurodegenerative conditions and dementia, shifting focus towards methods of prevention, with lifestyle approaches such as nutrition representing a promising avenue for further development. This overview summarises the main themes discussed during the 3 Symposium on "Nutrition for the Ageing Brain: Moving Towards Clinical Applications" held in Madrid in August 2018, enlarged with the current state of knowledge on how nutrition influences healthy ageing and gives recommendations regarding how the critical field of nutrition and neurodegeneration research should move forward into the future. Specific nutrients are discussed as well as the impact of multi-nutrient and whole diet approaches, showing particular promise to combatting the growing burden of age-related cognitive decline. The emergence of new avenues for exploring the role of diet in healthy ageing, such as the impact of the gut microbiome and development of new techniques (imaging measures of brain metabolism, metabolomics, biomarkers) are enabling researchers to approach finding answers to these questions. But the translation of these findings into clinical and public health contexts remains an obstacle due to significant shortcomings in nutrition research or pressure on the scientific community to communicate recommendations to the general public in a convincing and accessible way. Some promising programs exist but further investigation to improve our understanding of the mechanisms by which nutrition can improve brain health across the human lifespan is still required.
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http://dx.doi.org/10.1016/j.arr.2020.101079DOI Listing
September 2020

Consumption of Nuts at Midlife and Healthy Aging in Women.

J Aging Res 2020 7;2020:5651737. Epub 2020 Jan 7.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background: Nut consumption may reduce age-related diseases and lead to better health and well-being in aging. Many conditions of aging develop over decades, and thus earlier lifestyle factors may particularly influence later health.

Methods: In 1998 and 2002, we administered food frequency questionnaires to assess nut consumption (peanuts, walnuts, and other nuts and peanut butter) in women in the Nurses' Health Study in their 50 s/early 60 s. In 2012, those who survived beyond 65 years with no chronic diseases, no reported memory impairment, no physical disabilities, and intact mental health were considered "healthy agers." We used multivariable logistic regression to estimate odds ratios for healthy versus usual aging, controlled for sociodemographic, behavioral, dietary, and other potential confounding factors.

Results: Of 33,931 participants at midlife, 16% became "healthy agers." After age adjustment, we observed a significant association between total nut consumption at midlife and higher odds of healthy aging, with strongest associations observed excluding peanut butter (odds ratio (OR) = 1.46, 95% confidence interval (CI) 1.32-1.62, ≥3 servings/week versus none). Findings were attenuated after further control for covariates, including overall diet quality (OR = 1.14, 95% CI 1.02-1.28, trend = 0.05). For nut types, we found statistically significantly higher odds of healthy aging across peanuts, walnuts, and other nuts after age adjustment. After full control for confounders, only walnut consumption remained associated with healthy aging ( trend = 0.0001); for example, the OR was 1.20 (95% CI 1.00-1.44) for ≥2 servings/week versus none.

Conclusions: Women consuming nuts at midlife have a greater likelihood of overall health and well-being at older ages. Nut consumption may represent a simple intervention to explore and promote healthy aging.
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http://dx.doi.org/10.1155/2020/5651737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199627PMC
January 2020

Long-term hypercortisolism induces lipogenesis promoting palmitic acid accumulation and inflammation in visceral adipose tissue compared with HFD-induced obesity.

Am J Physiol Endocrinol Metab 2020 06 21;318(6):E995-E1003. Epub 2020 Apr 21.

Group of Endocrine Disorders, IDIBAPS, Barcelona, Spain.

Glucocorticoids (GCs) play critical roles in adipose tissue metabolism. Here, we compare in a mouse model the effects of chronic glucocorticoid excess and diet-induced obesity on white adipose tissue mass and distribution, by focusing on visceral adipose tissue (VAT) fatty acid composition changes, the role of de novo lipogenesis (DNL) and the inflammatory state. We used a noninvasive mouse model of hypercortisolism to compare GC-induced effects on adipose tissue with diet-induced obesity [high-fat diet (HFD) 45%] and control mice after 10 wk of treatment. Subcutaneous adipose tissue (SAT) and VAT mass and distribution were measured by nuclear magnetic resonance imaging (NMRI). Fatty acid composition in VAT was analyzed by NMR spectroscopy and gas chromatography. Gene expression of key enzymes involved in DNL was analyzed in liver and VAT. Macrophage infiltration markers and proinflammatory cytokines were measured by gene expression in VAT. HFD or GC treatment induced similar fat mass expansion with comparable distribution between SAT and VAT depots. However, in VAT, GCs induce DNL, higher palmitic acid (PA), macrophage infiltration, and proinflammatory cytokine levels, accompanied by systemic nonesterified fatty acid (NEFA) elevation, hyperinsulinemia, and higher homeostatic model assessment for insulin resistance (HOMA-IR) levels compared with diet-induced obesity. Thus, chronic hypercortisolism induces DNL and fatty acid composition changes toward increased SFA and reduced polyunsaturated fatty acid (PUFA) levels in VAT, promoting macrophage recruitment and proinflammatory cytokines, suggesting a worse cardiometabolic profile even compared with HFD mice.
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http://dx.doi.org/10.1152/ajpendo.00516.2019DOI Listing
June 2020

The Mediterranean diet decreases prothrombotic microvesicle release in asymptomatic individuals at high cardiovascular risk.

Clin Nutr 2020 11 27;39(11):3377-3384. Epub 2020 Feb 27.

Cardiovascular Program ICCC, Institut de Recerca Hospital Santa Creu i Sant Pau - IIB Sant Pau, Barcelona, Spain; CIBER Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Electronic address:

Background & Aims: Circulating microvesicles (cMV) are small phospholipid-rich vesicles that contribute to the atherothrombotic process, and are biomarkers of cardiovascular disease (CVD) burden and progression. Diet is a cornerstone for CVD prevention, but dietary effects on cMV shedding are poorly characterized. We aimed at assessing the long term effects of a Mediterranean diet compared to a low-fat diet (LFD) on MV shedding by cells of the blood and vascular compartments in patients at high cardiovascular risk treated as per guidelines.

Methods: A total of 155 participants from the PREDIMED trial free of cardiovascular events after a mean follow-up of 5 years (n = 53 from the Mediterranean diet supplemented with extra-virgin olive oil -EVOO-; n = 49 from the Mediterranean diet supplemented with mixed nuts -Nuts-; and n = 53 from the LFD) were included in the study. At baseline and after one-year intervention, cMV were quantified and characterized by flow cytometry to identify their activated parental cell origin and prothrombotic potential by Annexin V (AV) binding.

Results: After one year of dietary intervention, platelet-derived PAC-1/AV and CD62P/AV cMV concentrations were lower in the Nuts group compared with the LFD and EVOO interventions (P = 0.036 and 0.003, respectively). In addition, prothrombotic cMV carrying tissue factor (CD142/AV) and CD11a/AV cMV derived from activated cells, were significantly lower in both Mediterranean diet (EVOO and Nuts) interventions compared to one year of LFD (P < 0.0001 and 0.028, respectively). SMAα/AV cMV were lower in the LFD compared to the Nuts group after one year of intervention (P = 0.038).

Conclusions: cMV are markers of cell activation and vascular injury that appear to be sensitive to dietary changes. Following a Mediterranean diet rich in EVOO or nuts is associated with lower cell activation towards a pro-atherothrombotic phenotype, suggesting a delay in the development of CV complications.
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http://dx.doi.org/10.1016/j.clnu.2020.02.027DOI Listing
November 2020

Effect of a 2-year diet intervention with walnuts on cognitive decline. The Walnuts And Healthy Aging (WAHA) study: a randomized controlled trial.

Am J Clin Nutr 2020 03;111(3):590-600

Lipid Clinic, Endocrinology and Nutrition Service, Hospital Clínic, Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Background: Walnut consumption counteracts oxidative stress and inflammation, 2 drivers of cognitive decline. Clinical data concerning effects on cognition are lacking.

Objectives: The Walnuts And Healthy Aging study is a 2-center (Barcelona, Spain; Loma Linda, CA) randomized controlled trial examining the cognitive effects of a 2-y walnut intervention in cognitively healthy elders.

Methods: We randomly allocated 708 free-living elders (63-79 y, 68% women) to a diet enriched with walnuts at ∼15% energy (30-60 g/d) or a control diet (abstention from walnuts). We administered a comprehensive neurocognitive test battery at baseline and 2 y. Change in the global cognition composite was the primary outcome. We performed repeated structural and functional brain MRI in 108 Barcelona participants.

Results: A total of 636 participants completed the intervention. Besides differences in nutrient intake, participants from Barcelona smoked more, were less educated, and had lower baseline neuropsychological test scores than those from Loma Linda. Walnuts were well tolerated and compliance was good. Modified intention-to-treat analyses (n = 657) uncovered no between-group differences in the global cognitive composite, with mean changes of -0.072 (95% CI: -0.100, -0.043) in the walnut diet group and -0.086 (95% CI: -0.115, -0.057) in the control diet group (P = 0.491). Post hoc analyses revealed significant differences in the Barcelona cohort, with unadjusted changes of -0.037 (95% CI: -0.077, 0.002) in the walnut group and -0.097 (95% CI: -0.137, -0.057) in controls (P = 0.040). Results of brain fMRI in a subset of Barcelona participants indicated greater functional network recruitment in a working memory task in controls.

Conclusions: Walnut supplementation for 2 y had no effect on cognition in healthy elders. However, brain fMRI and post hoc analyses by site suggest that walnuts might delay cognitive decline in subgroups at higher risk. These encouraging but inconclusive results warrant further investigation, particularly targeting disadvantaged populations, in whom greatest benefit could be expected.This trial was registered at clinicaltrials.gov as NCT01634841.
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http://dx.doi.org/10.1093/ajcn/nqz328DOI Listing
March 2020

Parallel declines in erythrocyte trans fatty acids and US fatal ischemic heart disease rates.

Nutr Res 2019 11 30;71:111-114. Epub 2019 Oct 30.

OmegaQuant Analytics, LLC. Sioux Falls, SD, USA; Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA. Electronic address:

Ischemic heart disease (IHD) is a leading cause of mortality in the United States. There is substantial evidence that a sustained intake of industrially-produced trans fatty acids (IP-TFA) is associated with increased risk of fatal IHD. This has led many regulatory agencies to pressure dietary oil producers to remove IP-TFA from their products. That this has resulted in lower blood levels of IP-TFA in the United States is clear, but whether this has been accompanied by a reduction in the incidence of fatal IHD is unknown. To test the hypothesis that declining IP-TFA levels are associated with declining rates of fatal IHD, we compared the IP-TFA levels in red blood cells (RBC) analyzed in our laboratory between 2009 and 2016 (n = 53 194) with yearly US-specific IHD mortality rates. We found that decreasing RBC IP-TFA levels were strongly correlated with decreasing rates of fatal IHD (R = 0.9552, P < .0001). Recognizing the limitations of observational studies in addressing causation questions, our findings nevertheless support our hypothesis and suggest that efforts to remove IP-TFA from the food supply in the United States may be having the desired effect.
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http://dx.doi.org/10.1016/j.nutres.2019.09.010DOI Listing
November 2019

Plant-Rich Dietary Patterns, Plant Foods and Nutrients, and Telomere Length.

Adv Nutr 2019 11;10(Suppl_4):S296-S303

BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.

The world's population is aging as a consequence of an increased global life expectancy. Identifying simple strategies to promote healthy aging (i.e., absence of major chronic diseases, preserved physical and cognitive functions, intact mental health, and good quality of life) have emerged as a major public health concern. Identifying biomarkers to better characterize the aging process is a research priority. Telomeres are repetitive DNA sequences at chromosome ends that prevent the loss of genomic DNA, protecting its physical integrity. Telomere length (TL) is considered a biomarker of aging: shorter telomeres are associated with a decreased life expectancy and increased rates of age-related chronic diseases. Telomere attrition has been shown to be accelerated by oxidative stress and inflammation. Since edible plants contain plenty of compounds with antioxidant and anti-inflammatory properties, it is plausible that their sustained consumption might help counteract telomere attrition. In this narrative review, we update evidence on the association between plant-rich dietary patterns and plant-based foods and TL. First, we summarize findings from observational studies on the association between TL and 1) adherence to plant-rich dietary patterns (mainly, but not only, focused on the Mediterranean diet); 2) consumption of seeds (mostly focused on nuts, grains, and coffee); and 3) intake of carotenoids, one of the plant-derived bioactives most studied in health and disease. Second, we summarize the main randomized controlled trials evaluating the effect on TL of dietary interventions involving either plant-rich dietary patterns or plant foods. Even though evidence from trials is very limited, several observational studies have reinforced the suggestive benefits of adherence to the Mediterranean diet (a plant-rich dietary pattern), consumption of seeds (and its derivatives), and dietary intake of carotenoids on TL, which further supports the research benefits of plant-rich dietary patterns and plant foods to promote health and longevity.
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http://dx.doi.org/10.1093/advances/nmz026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855941PMC
November 2019

Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: A proof of concept study.

Metabolism 2019 12 9;101:154005. Epub 2019 Nov 9.

Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) affects 25-30% of the general population and is characterized by the presence of non-alcoholic fatty liver (NAFL) that can progress to non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis leading to hepatocellular carcinoma. To date, liver biopsy is the gold standard for the diagnosis of NASH and for staging liver fibrosis. This study aimed to train models for the non-invasive diagnosis of NASH and liver fibrosis based on measurements of lipids, glycans and biochemical parameters in peripheral blood and with the use of different machine learning methods.

Methods: We performed a lipidomic, glycomic and free fatty acid analysis in serum samples of 49 healthy subjects and 31 patients with biopsy-proven NAFLD (15 with NAFL and 16 with NASH). The data from the above measurements combined with measurements of 4 hormonal parameters were analyzed with two different platforms and five different machine learning tools.

Results: 365 lipids, 61 glycans and 23 fatty acids were identified with mass-spectrometry and liquid chromatography. Robust differences in the concentrations of specific lipid species were observed between healthy, NAFL and NASH subjects. One-vs-Rest (OvR) support vector machine (SVM) models with recursive feature elimination (RFE) including 29 lipids or combining lipids with glycans and/or hormones (20 or 10 variables total) could differentiate with very high accuracy (up to 90%) between the three conditions. In an exploratory analysis, a model consisting of 10 lipid species could robustly discriminate between the presence of liver fibrosis or not (98% accuracy).

Conclusion: We propose novel models utilizing lipids, hormones and glycans that can diagnose with high accuracy the presence of NASH, NAFL or healthy status. Additionally, we report a combination of lipids that can diagnose the presence of liver fibrosis. Both models should be further trained prospectively and validated in large independent cohorts.
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http://dx.doi.org/10.1016/j.metabol.2019.154005DOI Listing
December 2019
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