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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.

The mechanisms underlying the lipid-lowering effect of nuts remain elusive. This study explores whether one-year supplementation with walnuts decreases LDL-cholesterol (LDL-C) by affecting the expression of circulating microRNAs (c-miRNA). In this sub-study of the Walnuts and Healthy Aging (WAHA) trial, we obtained fasting serum at baseline and at 1 year from 330 free-living participants (63-79 year, 68% women), allocated into a control group (CG, abstinence from walnuts, n = 164) and a walnut group (WG, 15% of daily energy as walnuts, ~30-60 g/d, n = 166). Participants in the WG showed a 1 year decrease in LDL-C (-9.07, (95% confidence interval: -12.87; -5.73) mg/dL; p = 0.010 versus changes in the CG). We conducted a miRNA array in eight randomly selected participants in the WG who decreased in LDL-C. This yielded 53 c-miRNAs with statistically significant changes, 27 of which survived the correction for multiple testing. When validating them in the full population, statistical significance lasted for hsa-miR-551a, being upregulated in the WG. In mediation analysis, the change in hsa-miR-551a was unrelated to LDL-C decrease. Long-term supplementation with walnuts decreased LDL-C independently of the changes in c-miRNA. The hsa-miR-551a upregulation, which has been linked to a reduced cell migration and invasion in several carcinomas, suggests a novel mechanism of walnuts in cancer risk. This work was supported by a grant from the California Walnut Commission, Folsom, CA, US (to J.S. and E.R.), by a “Manuel de Hoya” grant (2014) from the Sociedad Española de Arteriosclerosis, and by Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (grant no. PI15/01014) (all to A.S.-V.). M.-C.L.d.l.H. was supported by a post-doctoral research contract funded by the community of Madrid and the European Union (PEJD-2016/BIO-2781). A.G.-R. acknowledges the Marie Curie AMAROUT-II Europe Program. A.D. was supported by the Spanish Agencia Estatal de Investigación and European Feder Funds (AGL2016-78922-R) and Fundación Ramón Areces (CIVP18A3888), Madrid, Spain. These funding agencies had no input in the study design, data collection, analyses, or writing and submission of the manuscript.

Despite the well-described deleterious effects of aging on cognition, some individuals are able to show stability. Here, we aimed to describe the functional and structural brain characteristics of older individuals, particularly focusing on those with stable working memory (WM) performance, as measured with a verbal N-back task across a 2-year follow-up interval. Forty-seven subjects were categorized as stables or decliners based on their WM change. Stables were further subdivided into high performers (SHP) and low performers (SLP), based on their baseline scores. At both time points, magnetic resonance imaging (MRI) data were acquired, including task-based functional MRI (fMRI) and structural T1-MRI. Although there was no significant interaction between overall stables and decliners as regards fMRI patterns, decliners exhibited over-activation in the right superior parietal lobule at follow-up as compared to baseline, while SHP showed reduced the activity in this region. Further, at follow-up, decliners exhibited more activity than SHP but in left temporo-parietal cortex and posterior cingulate (i.e., non-task-related areas). Also, at the cross-sectional level, SLP showed lower activity than SHP at both time points and less activity than decliners at follow-up. Concerning brain structure, a generalized significant cortical thinning over time was identified for the whole sample. Notwithstanding, the decliners evidenced a greater rate of atrophy comprising the posterior middle and inferior temporal gyrus as compared to the stable group. Overall, fMRI data suggest unsuccessful compensation in the case of decliners, shown as increases in functional recruitment during the task in the context of a loss in WM performance and brain atrophy. On the other hand, among older individuals with WM cognitive stability, differences in baseline performance might determine dissimilar fMRI trajectories. In this vein, the findings in the SHP subgroup support the brain maintenance hypothesis, suggesting that stable and high WM performance in aging is sustained by functional efficiency and maintained brain structure rather than compensatory changes.

Nut consumption lowers blood cholesterol and is associated with reduced cardiovascular disease, but effects on blood pressure (BP) are inconsistent. We assessed the 2-year effects of a walnut diet versus a control diet on office BP and 24-hours ambulatory BP in free-living elders participating in the Walnuts and Healthy Aging study, a randomized trial testing the effects of walnuts at ≈15% energy on age-related disorders. In a prespecified analysis, we enrolled 305 participants, of whom 236 (75%) completed the study (65% women; age, 69 years; 60% with mild hypertension). Walnuts were well tolerated, and compliance was >98%. Mean baseline office BP was 128/79 mm Hg. Adjusted changes from baseline in mean office systolic BP were −4.61 mm Hg (95% CI, −7.43 to −1.79 mm Hg) in the walnut group and −0.59 mm Hg (−3.38 to 2.21 mm Hg) in controls ( P =0.051). Respective changes in mean systolic 24-hour ambulatory BP were −3.86 mm Hg (CI, −5.45 to −2.26 mm Hg) and −2.00 mm Hg (CI, −3.58 to −0.42 mm Hg; P =0.111). No changes in diastolic BP were observed. In participants in the upper tertile of baseline 24-hour ambulatory systolic BP (>125 mm Hg), mean 2-year systolic 24-hour BP was −8.5 mm Hg (CI, −12 to −5.0 mm Hg) in the walnut group and −2.5 mm Hg (CI, −6.3 to 1.3 mm Hg) in controls ( P =0.034). During the trial, participants in the walnut group required less uptitration of antihypertensive medication and had better overall BP regulation than controls. Walnut consumption reduces systolic BP in elderly subjects, particularly in those with mild hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01634841 .

The combination of transcranial direct current stimulation (tDCS) with functional magnetic resonance imaging (fMRI) can provide original data to investigate age-related brain changes. We examined neural activity modulations induced by two multifocal tDCS procedures based on two distinct montages fitting two N-back task-based fMRI patterns ("compensatory" and "maintenance") related to high working memory (WM) in a previous publication (Fernández-Cabello et al. Neurobiol Aging (2016);48:23-33). We included 24 participants classified as stable or decliners according to their 4-year WM trajectories following a retrospective longitudinal approach. Then, we studied longitudinal fMRI differences between groups (stable and decliners) and across multifocal tDCS montages ("compensatory" and "maintenance") applied using a single-blind sham-controlled cross-over design. Decliners evidenced over-activation of non-related WM areas after 4 years of follow-up. Focusing on tDCS effects, among the decliner group, the "compensatory"-tDCS montage reduced the activity over the posterior regions where these subjects showed longitudinal hyperactivation. These results reinforce the notion that tDCS effects are characterized by an activity reduction and might be more noticeable in compromised systems. Importantly, the data provide novel evidence that cognitive trajectories predict tDCS effects in older adults.

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., Fundacion Ramon Areces (CIVP18A3888) Madrid, Spain; the Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria–Fondo Europeo de Desarrollo Regional (grant PI15/01014 and PI18/01152), and the Spanish Agencia Estatal de Investigacion and European Feder Funds (AGL2016-78922-R, PID2019-109369RB-I00, RTI2018-093873-A-I00 and BIO2017-86500-R). AS-V is recipient of the Instituto de Salud Carlos III Miguel Servet II fellowship (grant CP II 17/00029)

Neuroimaging investigations have revealed interindividual variations in anatomy, metabolism, activity, and connectivity of specific cortical association areas through which years of education (YoE), as a common proxy of cognitive reserve, may operate in the face of age- or pathology-associated brain changes. However, the associated molecular properties of YoE-related brain regions and the biological pathways involved remain poorly understood. In the present study we first identified brain areas that showed an association between cortical thickness and YoE among 122 cognitively healthy older human individuals (87 female). We subsequently characterized molecular properties of these regions by studying brain-wide microarray measurements of regional gene expression. In accordance with previous studies, we observed that YoE were associated with higher cortical thickness in medial prefrontal, anterior cingulate, and orbitofrontal areas. Compared with the rest of the cortex, these regions exhibited a distinct gene expression profile characterized by relative upregulation of gene sets implicated in ionotropic and metabotropic neurotransmission as well as activation of immune response. Our genome-wide expression profile analysis of YoE-related brain regions points to distinct molecular pathways that may underlie a higher capacity for plastic changes in response to lifetime intellectual enrichment and potentially also a higher resilience to age-related pathologic brain changes. SIGNIFICANCE STATEMENT We combined a neuroimaging-based analysis with a transcriptome-wide gene expression approach to investigate the molecular-functional properties of cortical regions associated with educational attainment, as a commonly used proxy for cognitive reserve, in older individuals. The strongest association with education was observed in specific areas of the medial prefrontal cortex, and these areas exhibited a distinct gene expression profile characterized by relative upregulation of gene sets implicated in neurotransmission and immune responses. These findings complement previous neuroimaging studies in the field and point to novel biological pathways that may mediate the beneficial effects of high educational attainment on adaptability to cope with, or prevent, age-related brain changes. The identified genes and pathways now warrant further exploration in mechanistic studies.

Supplemental Digital Content is available in the text., Nut consumption lowers blood cholesterol and is associated with reduced cardiovascular disease, but effects on blood pressure (BP) are inconsistent. We assessed the 2-year effects of a walnut diet versus a control diet on office BP and 24-hours ambulatory BP in free-living elders participating in the Walnuts and Healthy Aging study, a randomized trial testing the effects of walnuts at ≈15% energy on age-related disorders. In a prespecified analysis, we enrolled 305 participants, of whom 236 (75%) completed the study (65% women; age, 69 years; 60% with mild hypertension). Walnuts were well tolerated, and compliance was >98%. Mean baseline office BP was 128/79 mm Hg. Adjusted changes from baseline in mean office systolic BP were −4.61 mm Hg (95% CI, −7.43 to −1.79 mm Hg) in the walnut group and −0.59 mm Hg (−3.38 to 2.21 mm Hg) in controls (P=0.051). Respective changes in mean systolic 24-hour ambulatory BP were −3.86 mm Hg (CI, −5.45 to −2.26 mm Hg) and −2.00 mm Hg (CI, −3.58 to −0.42 mm Hg; P=0.111). No changes in diastolic BP were observed. In participants in the upper tertile of baseline 24-hour ambulatory systolic BP (>125 mm Hg), mean 2-year systolic 24-hour BP was −8.5 mm Hg (CI, −12 to −5.0 mm Hg) in the walnut group and −2.5 mm Hg (CI, −6.3 to 1.3 mm Hg) in controls (P=0.034). During the trial, participants in the walnut group required less uptitration of antihypertensive medication and had better overall BP regulation than controls. Walnut consumption reduces systolic BP in elderly subjects, particularly in those with mild hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01634841.

[Background]: Inflammation is known to be related to the leading causes of death including cardiovascular disease, several types of cancer, obesity, type 2 diabetes, depression-suicide and other chronic diseases. In the context of whole dietary patterns, the Dietary Inflammatory Index (DII®) was developed to appraise the inflammatory potential of the diet. [Objective]: We prospectively assessed the association between DII scores and all-cause mortality in two large Spanish cohorts and valuated the consistency of findings across these two cohorts and results published based on other cohorts., [Design]: We assessed 18,566 participants in the “Seguimiento Universidad de Navarra” (SUN) cohort followed-up during 188,891 person-years and 6790 participants in the “PREvencion con DIeta MEDiterránea” (PREDIMED) randomized trial representing 30,233 person-years of follow-up. DII scores were calculated in both cohorts from validated FFQs. Higher DII scores corresponded to more proinflammatory diets. A total of 230 and 302 deaths occurred in SUN and PREDIMED, respectively. In a random-effect meta-analysis we included 12 prospective studies (SUN, PREDIMED and 10 additional studies) that assessed the association between DII scores and all-cause mortality., [Results]: After adjusting for a wide array of potential confounders, the comparison between extreme quartiles of the DII showed a positive and significant association with all-cause mortality in both the SUN (hazard ratio [HR] = 1.85; 95% CI: 1.15, 2.98; P-trend = 0.004) and the PREDIMED cohort (HR = 1.42; 95% CI: 1.00, 2.02; P-trend = 0.009). In the meta-analysis of 12 cohorts, the DII was significantly associated with an increase of 23% in all-cause mortality (95% CI: 16%–32%, for the highest vs lowest category of DII)., [Conclusion]: Our results provide strong and consistent support for the hypothesis that a pro-inflammatory diet is associated with increased all-cause mortality. The SUN cohort and PREDIMED trial were registered at clinicaltrials.gov as NCT02669602 and at isrctn.com as ISRCTN35739639, respectively., Supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140, to R.E.; RTIC RD 06/0045, to Miguel A. Martínez-González) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (Proyecto de Investigación (PI) 04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, PI13/00615, PI13/01090, PI14/01668, PI14/01798, PI14/01764), Ministerio de Ciencia e Innovación (Recursos y teconologia agroalimentarias(AGL)-2009-13906-C02 and AGL2010-22319-C03 and AGL2013-49083-C3-1- R), Fundación Mapfre 2010, the Consejería de Salud de la Junta de Andalucía (PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (Generalitat Valenciana Ayuda Complementaria (GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151), Conselleria de Sanitat y, PI14/01764 AP; Atención Primaria (CS) 2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011).). Drs. Shivappa and Hébert were supported by grant number R44DK103377 from the United States National Institute of Diabetes and Digestive and Kidney Diseases.

Randomized controlled trials on diet and shortening of leukocyte telomere length (LTL) mostly focus on marine-derived n-3 polyunsaturated fatty acids (PUFA). Walnuts are a sustainable source of n-3 PUFA. We investigated whether inclusion of walnuts (15% of energy) in the diet for 2 years would maintain LTL in cognitively healthy elders (63&ndash, 79 years old) compared to a control group (habitual diet, abstaining from walnuts). This opportunistic sub-study was conducted within the Walnuts and Healthy Aging study, a dual-centre (Barcelona, Spain and Loma Linda University, California) parallel trial. A sub-set of the Barcelona site participants were randomly assigned to the walnut (n = 80) or control group (n = 69). We assessed LTL at baseline and at 2 years and we conducted repeated-measures ANCOVA with 2 factors: time (baseline, 2 years) and group (control, walnut) and their interaction. Adjusted means (95% confidence interval) of LTL (in kb) in controls were 7.360 (7.084,7.636) at baseline and 7.061 (6.835,7.288) after 2 years, corresponding values in the walnut group were 7.064 (6.807,7.320) and 7.074 (6.864,7.284). The time &times, intervention interaction was nearly significant (p = 0.079), suggestive of a trend of walnut consumption in preserving LTL. This exploratory research finding should be confirmed in trials with adequate statistical power.

Background & aims: Legumes, a low-energy, nutrient-dense and low glycemic index food, have shown beneficial effects on glycemic control and adiposity. As such, legumes are widely recommended in diabetic diets, even though there is little evidence that their consumption protects against type 2 diabetes. Therefore the aim of the present study was to examine the associations between consumption of total legumes and specific subtypes, and type 2 diabetes risk. We also investigated the effect of theoretically substituting legumes for other protein- or carbohydrate-rich foods. Methods: Prospective assessment of 3349 participants in the PREvención con DIeta MEDiterránea (PREDIMED) study without type 2 diabetes at baseline. Dietary information was assessed at baseline and yearly during follow-up. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for type-2 diabetes incidence according to quartiles of cumulative average consumption of total legumes, lentils, chickpeas, dry beans and fresh peas. Results: During a median follow-up of 4.3 years, 266 new cases of type 2 diabetes occurred. Individuals in the highest quartile of total legume and lentil consumption had a lower risk of diabetes than those in the lowest quartile (HR: 0.65; 95% CI: 0.43, 0.96; P-trend = 0.04; and HR: 0.67; 95% CI: 0.46–0.98; P-trend = 0.05, respectively). A borderline significant association was also observed for chickpeas consumption (HR 0.68; 95% CI: 0.46, 1.00; P-trend = 0.06). Substitutions of half a serving/day of legumes for similar servings of eggs, bread, rice or baked potato was associated with lower risk of diabetes incidence. Conclusions: A frequent consumption of legumes, particularly lentils, in the context of a Mediterranean diet, may provide benefits on type 2 diabetes prevention in older adults at high cardiovascular risk. Trial registration: The trial is registered at http://www.controlled-trials.com (ISRCTN35739639). Registration date: 5th October 2005., The authors disclose no conflict of interest related with the article. Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds (CB06/03). Supported by the official funding agency for biomedical research of the Spanish government, ISCIII, through grants provided to research networks specifically developed for the trial (RTIC G03/140 and RD 06/0045) through CIBEROBN, and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–FondoEuropeo de Desarrollo Regional (PI04–2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and PI11/02505; PI13/00462), Ministerio de Ciencia e Innovación (AGL-2009–13906-C02 and AGL2010–22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, and CS2011-AP-042), and the Navarra Regional Government (27/2011). The Fundación Patrimonio Comunal Olivarero and Hojiblanca SA (Málaga, Spain), California Walnut Commission (Sacramento, CA), Borges SA (Reus, Spain), and Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study. None of the funding sources played a role in the design, collection, analysis or interpretation of the data or in the decision to submit the manuscript for publication. Acknowledgements: The authors thank all the participants for their collaboration, all the PREDIMED personnel for their assistance and all the personnel of affiliated primary care centers for making the study possible. CIBEROBN is an initiative of ISCIII, Spain.

Previous studies have reported an association between a more pro-inflammatory diet profile and various chronic metabolic diseases. The Dietary Inflammatory Index (DII) was used to assess the inflammatory potential of nutrients and foods in the context of a dietary pattern. We prospectively examined the association between the DII and the incidence of cardiovascular disease (CVD: myocardial infarction, stroke or cardiovascular death) in the PREDIMED (Prevención con Dieta Mediterránea) study including 7216 high-risk participants. The DII was computed based on a validated 137-item food frequency questionnaire. Multivariate-adjusted hazard ratios (HR) and 95% confidence intervals of CVD risk were computed across quartiles of the DII where the lowest (most anti-inflammatory) quartile is the referent. Risk increased across the quartiles (i.e., with increasing inflammatory potential): HRquartile2 = 1.42 (95%CI = 0.97–2.09), HRquartile3 = 1.85 (1.27–2.71), and HRquartile4 = 1.73 (1.15–2.60). When fit as continuous the multiple-adjusted hazard ratio for each additional standard deviation of the DII was 1.22 (1.06–1.40). Our results provide direct prospective evidence that a pro-inflammatory diet is associated with a higher risk of cardiovascular clinical events.

Summary Background & aims Shortening of leukocyte telomere length (LTL) is a biomarker of aging. Epidemiologic studies of LTL in relation to dietary fatty acids have reported conflicting results. The red blood cell (RBC) fatty acid status is a valid objective biomarker of long-term dietary intake of C18:2n-6, C18:3n-3 and long-chain n-3 polyunsaturated fatty acids (C20:5n-3 and C22:6n-3). In healthy older individuals, we investigated whether LTL relates to the RBC proportions of the main dietary polyunsaturated fatty acids (PUFA), and to the RBC proportion of arachidonic acid (C20:4n-6), a fatty acid that can generate pro-inflammatory lipid mediators once released from cell membranes. Design Cross-sectional study in 344 subjects (mean age 68.8 y, 68.6% women) who participated in a randomized controlled trial testing whether a diet enriched in walnuts can delay the onset of age-related diseases ( https://clinicaltrials.gov/ct2/show/NCT01634841 ). At baseline, we assessed LTL by high-throughput quantitative fluorescence and determined fatty acids in RBCs by gas chromatography. Results In multivariate models adjusted for age and gender, the RBC proportions of dietary PUFA were unrelated to LTL. In contrast, the RBC proportion of arachidonic acid inversely related to LTL (regression coefficient [95% confidence interval], −0.10 (−0.19 to −0.01), P = 0.023). Conclusion An increasing proportion of C20:4n-6 in RBCs is associated with shorter telomeres. Further research is needed to investigate the role of this fatty acid and its derived lipid mediators in the aging process.

Background: Subjective cognitive decline (SCD) is gaining importance as a focus of investigation, but adequate tools are needed for its quantification. Objective: To develop and validate a questionnaire to quantify SCD, termed the Subjective Cognitive Decline Questionnaire (SCD-Q). Methods: 124 controls (CTR), 144 individuals with SCD, 83 mild cognitive impairment subjects, 46 Alzheimer's disease patients, and 397 informants were included. The SCD-Q contains: part I, named MyCog, which is answered by the subject; and part II, TheirCog, which includes the same questions and is answered by the informant or caregiver. The 24 SCD-Q items assess the perceived subjective decline in memory, language, and executive functions in the last two years. Results: The MyCog scores of controls differed significantly from those of the other groups (p < 0.05) and there were significant differences in TheirCog scores between all groups. The optimal TheirCog cut-off score for discriminating between individuals with and without cognitive impairment was 7/24 (sensitivity 85%, specificity 80%). MyCog scores correlated significantly with anxiety and depression (r = 0.29, r = 0.43, p < 0.005), but no correlations were found with neuropsychological tests. TheirCog scores correlated significantly with most of the neuropsychological tests (p < 0.05). Informants' depression and anxiety influenced TheirCog scores in controls and SCD groups. Conclusion: Self-perceived cognitive decline, measured by the SCD-Q part I (MyCog), discriminated SCD from CTR. Part II (TheirCog) was strongly related to subjects' objective cognitive performance, and discriminated between subjects with or without cognitive impairment. The SCD-Q is a useful tool to measure self-perceived cognitive decline incorporating the decliner and the informant perspective.

Cognitive reserve (CR) models posit that lifestyle factors such as education modulate the relationship between brain damage and cognition. However, the functional correlates of CR in healthy aging are still under investigation. White matter hyperintensities (WMHs) are a common age-associated finding that impacts cognition. In this study, we used functional magnetic resonance imaging to characterize the patterns of brain activation during a working memory task in older participants with high and low levels of education (as a proxy of CR) and high and low WMH volumes. Ninety older volunteers (aged 63-76 years) and 16 young adults (aged 21-27) completed the study. We found that older adults with higher education had better working memory performance than their less educated peers. Among the highly educated participants, those with WMH over-recruited areas engaged by young volunteers and showed activation in additional cortical and subcortical structures. However, those with low WMH differed little with respect to their younger counterparts. Our findings demonstrate that the functional mechanisms subtending the effects of education, as a proxy of CR, are modulated according to the WMH burden.

IMPORTANCE: Diabetic retinopathy (DR) is a devastating complication of individuals with type 2 diabetes mellitus. The retina is rich in long-chain ω−3 polyunsaturated fatty acids (LCω3PUFAs), which are substrate for oxylipins with anti-inflammatory and antiangiogenic properties. Experimental models support dietary LCω3PUFA protection against DR, but clinical data are lacking. OBJECTIVE: To determine whether LCω3PUFA intake relates to a decreased incidence of sight-threatening DR in individuals with type 2 diabetes older than 55 years. DESIGN, SETTING, AND PARTICIPANTS: In late 2015, we conceived a prospective study within the randomized clinical trial Prevención con Dieta Mediterránea (PREDIMED), testing Mediterranean diets supplemented with extra virgin olive oil or nuts vs a control diet for primary cardiovascular prevention. The trial was conducted in primary health care centers in Spain. From 2003 to 2009, 3614 individuals aged 55 to 80 years with a previous diagnosis of type 2 diabetes were recruited. Full data were available for 3482 participants (48% men; mean age 67 years). EXPOSURES: Meeting the dietary LCω3PUFA recommendation of at least 500 mg/d for primary cardiovascular prevention, as assessed by a validated food-frequency questionnaire. MAIN OUTCOMES AND MEASURES: The main outcome was incident DR requiring laser photocoagulation, vitrectomy, and/or antiangiogenic therapy confirmed by an external adjudication committee. RESULTS: Of the 3482 participants, 48% were men and the mean age was 67 years. A total of 2611 participants (75%) met target LCω3PUFA recommendation. During a median follow-up of 6 years, we documented 69 new events. After adjusting for age, sex, intervention group, and lifestyle and clinical variables, participants meeting the LCω3PUFA recommendation at baseline (≥500 mg/d) compared with those not fulfilling this recommendation (

Brain oxidative processes play a major role in age-related cognitive decline, thus consumption of antioxidant-rich foods might help preserve cognition. Our aim was to assess whether consumption of antioxidant-rich foods in the Mediterranean diet relates to cognitive function in the elderly. In asymptomatic subjects at high cardiovascular risk (n = 447; 52% women; age 55-80 y) enrolled in the PREDIMED study, a primary prevention dietary-intervention trial, we assessed food intake and cardiovascular risk profile, determined apolipoprotein E genotype, and used neuropsychological tests to evaluate cognitive function. We also measured urinary polyphenols as an objective biomarker of intake. Associations between energy-adjusted food consumption, urinary polyphenols, and cognitive scores were assessed by multiple linear regression models adjusted for potential confounders. Consumption of some foods was independently related to better cognitive function. The specific associations [regression coefficients (95% confidence intervals)] were: total olive oil with immediate verbal memory [0.755 (0.151-1.358)]; virgin olive oil and coffee with delayed verbal memory [0.163 (0.010-0.316) and 0.294 (0.055-0.534), respectively]; walnuts with working memory [1.191 (0.061-2.322)]; and wine with Mini-Mental State Examination scores [0.252 (0.006-0.496)]. Urinary polyphenols were associated with better scores in immediate verbal memory [1.208 (0.236-2.180)]. Increased consumption of antioxidant-rich foods in general and of polyphenols in particular is associated with better cognitive performance in elderly subjects at high cardiovascular risk. The results reinforce the notion that Mediterranean diet components might counteract age-related cognitive decline.

Despite of the positive medical and scientific advances generated through the mild cognitive impairment (MCI) diagnosis, as we will see along this paper, the concept of MCI presents several major limitations. MCI defines a syndrome and therefore it may be the consequence of different diseases with distinct aetiologies. Furthermore, the philosophy behind the MCI scenario has been to detect a group of symptoms that eventually will evolve into a distinct disease. In contrast, our nowadays aim is to detect a disease in its earlier stages that eventually will evolve from one clinical syndrome to another. As an example, our aim now is to detect early AD that initially will manifest as a memory syndrome and eventually will evolve into a dementia syndrome. Consequently, in order to overcome the syndromical diagnosis behind MCI, the concept of prodromal AD (Prd-AD) has recently emerged. Prd-AD is defined as the symptomatic predementia phase of AD, generally included in the MCI category; this stage is characterised by symptoms not severe enough to meet currently accepted diagnostic criteria for AD. Being a nosological concept, it has several potential advantages related with early diagnosis and treatment, together with the possibility to contribute to the development of disease modifying drugs.

In the past few years, there has been an increasing awareness of the regional vulnerability of the hippocampus to age-related processes. However, to date, no studies have assessed the effects of age on different structural magnetic resonance parameters in the specific hippocampal subfields. In this study, we measured volume, mean diffusivity (MD) and fractional anisotropy (FA) in the presubiculum, subiculum, fimbria, cornu ammonis (CA) 1,2-3,4-DG and the whole hippocampus in fifty cognitively intact elder adults between 50 and 75 years of age (20 men, 30 women). Segmentation of hippocampal subfields was performed using FreeSurfer. Individual MD and FA images were coregistered to T1-weighted volumes using FLIRT of FSL. Linear regression analyses were performed to assess the effects of age on the anatomical measures of each subfield. In addition, multiple regression analyses were also carried out to assess which of the anatomical measures that showed a correlation with age in the previous analyses, were the best age predictors in the hippocampus. In agreement with previous studies, our results showed a significant association between age and volume (P 0.001) as well as MD (P 0.001) in the whole hippocampus. Regarding the specific hippocampal subfields, we found that age had a significant negative effect on volume in CA2-3 (P 0.001) and CA4-DG (P 0.001). Importantly, we found a positive effect of age on MD in CA2-3 (P 0.001) and fimbria (P 0.001) as well as a negative age effect on FA in the subiculum (P 0.001). Multiple regression analyses revealed that the best overall predictors of age in the hippocampus were MD in the fimbria and volume of CA2-3, which explained 73.8% of the age variance. These results indicate that age has an effect both on volume and diffusion tensor imaging measures in different subfields, suggesting they provide complementary information on age-related processes in the hippocampus.

The term cognitive reserve describes the capacity of the adult brain to minimise the clinical manifestation of a neurodegenerative process. The acquisition of cognitive reserve has been linked to the performance of certain intellectual and cognitive activities throughout the whole of the individual's life.To create a new cognitive reserve questionnaire (CRQ), to establish its relation with the cognitive functions and to obtain the standard values in the cognitively healthy elderly Spanish population.The sample consisted of 55 cognitively healthy controls and 53 patients with Alzheimer's disease. All the subjects were asked to complete the CRQ, which consists of eight items with several different possible answers, together with a brief neuropsychological battery.Age had no significant influence on the score obtained on the CRQ in either of the groups, yet the number of years of schooling did exert a significant effect. In both groups significant correlations were found between the score on the CRQ and performance in neuropsychological tests that measure executive functioning.The CRQ is a useful questionnaire for assessing the degree of cognitive reserve in healthy controls and in patients in the early stages of Alzheimer's disease. The CRQ is associated with the cognitive performance of executive functioning.

Because Alzheimer's disease (AD) needs to be treated as soon as possible after onset, its early detection has become one of the core areas of research in the field of neurodegenerative diseases.Attempts to characterise the incipient phases of the disease have evolved from the appearance of the heterogeneous concept of mild cognitive impairment in the last twentieth century to the diagnostic criteria proposed for AD by current research. These criteria make it possible to perform an early diagnosis of AD (in the prodromal phase) that is at the same time aetiological, since it is backed up by objective biological markers which will be discussed in this work. Additionally, the article will also review the concept of preclinical AD, which is supported by evidence showing that the pathological process of AD begins years before the clinical manifestation of the disease.To date, this preclinical phase is the one that has received less attention from researchers, although the development of complex imaging techniques with new tracers appears to be a promising beginning to the coveted path towards the preclinical diagnosis of the disease.

IMPORTANCE: Oxidative stress and vascular impairment are believed to partly mediate age-related cognitive decline, a strong risk factor for development of dementia. Epidemiologic studies suggest that a Mediterranean diet, an antioxidant-rich cardioprotective dietary pattern, delays cognitive decline, but clinical trial evidence is lacking. OBJECTIVE: To investigate whether a Mediterranean diet supplemented with antioxidant-rich foods influences cognitive function compared with a control diet. DESIGN, SETTING, AND PARTICIPANTS: Parallel-group randomized clinical trial of 447 cognitively healthy volunteers from Barcelona, Spain (233 women [52.1%]; mean age, 66.9 years), at high cardiovascular risk were enrolled into the Prevención con Dieta Mediterránea nutrition intervention trial from October 1, 2003, through December 31, 2009. All patients underwent neuropsychological assessment at inclusion and were offered retesting at the end of the study. INTERVENTIONS: Participants were randomly assigned to a Mediterranean diet supplemented with extravirgin olive oil (1 L/wk), a Mediterranean diet supplemented with mixed nuts (30 g/d), or a control diet (advice to reduce dietary fat). MAIN OUTCOMES AND MEASURES: Rates of cognitive change over time based on a neuropsychological test battery: Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT), Animals Semantic Fluency, Digit Span subtest from the Wechsler Adult Intelligence Scale, Verbal Paired Associates from the Wechsler Memory Scale, and the Color Trail Test. We used mean z scores of change in each test to construct 3 cognitive composites: memory, frontal (attention and executive function), and global. RESULTS: Follow-up cognitive tests were available in 334 participants after intervention (median, 4.1 years). In multivariate analyses adjusted for confounders, participants allocated to a Mediterranean diet plus olive oil scored better on the RAVLT (P = .049) and Color Trail Test part 2 (P = .04) compared with controls; no between-group differences were observed for the other cognitive tests. Similarly adjusted cognitive composites (mean z scores with 95% CIs) for changes above baseline of the memory composite were 0.04 (-0.09 to 0.18) for the Mediterranean diet plus olive oil, 0.09 (-0.05 to 0.23; P = .04 vs controls) for the Mediterranean diet plus nuts, and -0.17 (-0.32 to -0.01) for the control diet. Respective changes from baseline of the frontal cognition composite were 0.23 (0.03 to 0.43; P = .003 vs controls), 0.03 (-0.25 to 0.31), and -0.33 (-0.57 to -0.09). Changes from baseline of the global cognition composite were 0.05 (-0.11 to 0.21; P = .005 vs controls) for the Mediterranean diet plus olive oil, -0.05 (-0.27 to 0.18) for the Mediterranean diet plus nuts, and -0.38 (-0.57 to -0.18) for the control diet. All cognitive composites significantly (P

Introduccion. La reserva cognitiva define la capacidad del cerebro adulto de minimizar la manifestacion clinica de un proceso neurodegenerativo. La adquisicion de la reserva cognitiva se ha asociado a la realizacion de determinadas actividades intelectuales y cognitivas a lo largo de toda la vida. Objetivos. Crear un nuevo cuestionario de reserva cognitiva (CRC), establecer su relacion con las funciones cognitivas y obtener los valores normativos en la poblacion espanola anciana cognitivamente sana. Sujetos y metodos. 55 controles cognitivamente sanos y 53 pacientes con enfermedad de Alzheimer. A todos los sujetos se les administro el CRC, que consta de ocho items con varias opciones de respuesta, asi como una bateria neuropsicologica breve. Resultados. La edad no tuvo una influencia significativa en la puntuacion obtenida en el CRC en ninguno de los grupos; sin embargo, los anos de escolaridad si influyeron significativamente. En ambos grupos, se encontraron correlaciones significativas entre la puntuacion en el CRC y el rendimiento en pruebas neuropsicologicas que miden la funcion ejecutiva. Conclusiones. El CRC es un cuestionario util para evaluar el grado de reserva cognitiva en controles sanos y en pacientes con enfermedad de Alzheimer inicial. El CRC se asocia al rendimiento cognitivo de la funcion ejecutiva.

Introduccion. La memoria episodica visual se afecta en fases iniciales de la enfermedad de Alzheimer (EA). Objetivos. Disenar un test de memoria visual libre de contenido verbal, ofrecer sus valores normativos en la poblacion espanola anciana, validar el test en un grupo de pacientes con EA leve y determinar su capacidad de discriminacion entre sujetos con EA y controles. Sujetos y metodos. Se incluyo una muestra de 263 sujetos (137 controles y 126 pacientes con EA) mayores de 50 anos. El test de paisajes consta de una primera parte donde se muestran 25 fotografias de paisajes. Transcurridos cinco minutos, se presentan las 25 fotografias anteriores junto con 25 fotografias nuevas, y el sujeto debe reconocer aquellas vistas con anterioridad. Para el analisis estadistico se utilizaron las pruebas t de Student para medidas independientes, ANCOVA, regresion lineal, correlacion de Pearson y curva ROC. Resultados. En el grupo control, el sexo y la escolaridad no influyeron significativamente en los resultados, aunque si se encontraron diferencias entre el grupo mas joven (50-59 anos) y el de mayor edad (igual o mayor de 80 anos). Los resultados indican que existe diferencia significativa entre las puntuaciones medias del test de paisajes obtenidas por los dos grupos (control: 44,06 ± 3,2; EA: 34,25 ± 6,6; p < 0,001). El area bajo la curva del test de paisajes fue de 0,904, con una sensibilidad de 0,82 y una especificidad de 0,85. Conclusion. El test de paisajes es un instrumento sencillo, sensible y novedoso para la valoracion de la memoria visual en la EA inicial.

Introduccion. Debido a la necesidad de tratamientos para la enfermedad de Alzheimer (EA) en fases muy iniciales, su deteccion precoz se ha convertido en uno de los principales focos de investigacion en el campo de las enfermedades neurodegenerativas. Desarrollo. El intento de caracterizar las fases incipientes de la enfermedad ha evolucionado desde la aparicion del heterogeneo concepto de deterioro cognitivo leve a finales del siglo pasado hasta los actuales criterios diagnosticos de investigacion propuestos para la EA. Estos criterios permiten realizar un diagnostico precoz de la EA, en fase prodromica, y etiologico, al estar sustentado en marcadores biologicos objetivos, que se describiran a lo largo de este trabajo. Se revisara, ademas, el concepto de EA preclinica, que se sustenta en la evidencia de que el proceso patologico de la EA empieza anos antes de la manifestacion clinica de la enfermedad. Conclusiones. Por el momento, la fase preclinica es la menos estudiada, aunque el desarrollo de tecnicas complejas de imagen con nuevos trazadores supone un inicio prometedor del camino sonado hacia el diagnostico preclinico de la enfermedad.

Objetivos. Establecer la validez discriminativa del test minimental (MMSE) y del test de alteracion de memoria (T@M) para el diagnostico del deterioro cognitivo leve amnesico (DCLa) y la enfermedad de Alzheimer (EA) probable, y estudiar la asociacion entre los resultados obtenidos en pruebas de cribado, una bateria neuropsicologica y un cuestionario funcional en personas sanas y en pacientes con DCLa y EA. Sujetos y metodos. Se evaluo a 27 controles normales, 27 pacientes con DCLa y 35 pacientes con EA con el MMSE y con un test de cribado de memoria, el T@M, una bateria neuropsicologica y un cuestionario de actividades funcionales de la vida diaria. Los coeficientes de correlacion de Pearson se utilizaron para evaluar las relaciones entre las puntuaciones del T@M y el MMSE y los test neuropsicologicos. Se calcularon las areas bajo la curva, la sensibilidad y la especificidad para los test de cribado. Resultados. En los pacientes con DCLa, las puntuaciones en el T@M y el MMSE resultaron estar fuertemente asociadas con el rendimiento de test de memoria episodica de las pruebas frontales y con las puntuaciones del cuestionario funcional, pero no con pruebas que evaluaban praxias y funciones perceptivas. En los pacientes con EA, las puntuaciones en el T@M y el MMSE se asociaron con resultados en memoria semantica, lenguaje, funciones ejecutivas y praxias, pero no con pruebas perceptivas y cuestionarios funcionales. Conclusiones. En pacientes con DCLa y EA, la asociacion entre el MMSE y el T@M solamente correlaciona con algunas funciones cognitivas, sin que exista asociacion con otras funciones cognitivas. Por lo tanto, los test de cribado no pueden utilizarse como unico instrumento para evaluar el estado cognitivo en pacientes con sospecha de demencia.

Introduction: An unwanted consequence of population aging is the growing number of elderly at risk of neurodegenerative disorders, including dementia and macular degeneration. As nutritional and behavioral changes can delay disease progression, we designed the Walnuts and Healthy Aging (WAHA) study, a two-center, randomized, 2-year clinical trial conducted in free-living, cognitively healthy elderly men and women. Our interest in exploring the role of walnuts in maintaining cognitive and retinal health is based on extensive evidence supporting their cardio-protective and vascular health effects, which are linked to bioactive components, such as n-3 fatty acids and polyphenols. Methods: The primary aim of WAHA is to examine the effects of ingesting walnuts daily for 2 years on cognitive function and retinal health, assessed with a battery of neuropsychological tests and optical coherence tomography, respectively. All participants followed their habitual diet, adding walnuts at 15% of energy (≈30–60 g/day) (walnut group) or abstaining from walnuts (control group). Secondary outcomes include changes in adiposity, blood pressure, and serum and urinary biomarkers in all participants and brain magnetic resonance imaging in a subset. Results: From May 2012 to May 2014, 708 participants (mean age 69 years, 68% women) were randomized. The study ended in May 2016 with a 90% retention rate. Discussion: The results of WAHA might provide high-level evidence of the benefit of regular walnut consumption in delaying the onset of age-related cognitive impairment and retinal pathology. The findings should translate into public health policy and sound recommendations to the general population (ClinicalTrials.gov identifier NCT01634841).