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Walnuts, long-chain polyunsaturated fatty acids, and adolescent brain development: Protocol for the walnuts smart snack dietary intervention trial.

Julvez, J., F. Gignac, S. Fernández-Barrés, D. Romaguera, A. Sala-Vila, O.T. Ranzani, C. Persavento, A. Delgado, A. Carol, J. Torrent, J. Gonzalez, E. Roso, J. Barrera-Gómez, M. López-Vicente, R. Garcia-Esteban, O. Boucher, J. Forns, M. Burgaleta, N. Sebastián, J. Canals, V. Arija, X. Basagaña, E. Ros, J. Vendrell, J. Salas-Salvadó, J. Sunyer, 2021. Walnuts, long-chain polyunsaturated fatty acids, and adolescent brain development: Protocol for the walnuts smart snack dietary intervention trial. Front. Pediatr. 9:593847. doi: 10.3389/fped.2021.593847

Background: 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. Methodology/Design: We conducted a 6-month population-based randomized controlled trial in teenagers (n = 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. Discussion: 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.

Walnut intake, cognitive outcomes and risk factors: a systematic review and meta-analysis.

Cahoon, D., S.P. Shertukde, E.E. Avendano, J. Tanprasertsuk, T.M. Scott, E.J. Johnson, M. Chung, N. Nirmala, 2021. Walnut intake, cognitive outcomes and risk factors: a systematic review and meta-analysis. Annals of Medicine, 53:1, 971-997, DOI: 10.1080/07853890.2021.1925955.

Background: Walnuts contain nutrients that are associated with improved cognitive health. To our knowledge, no review has systematically examined the effects of walnuts on cognitive function and risk for cognitive decline. Objective To conduct a systematic review and meta-analysis evaluating the effects of walnut intake on cognition-related outcomes and risk-factors for cognitive decline in adults. Methods: Medline®, Commonwealth Agricultural Bureau, and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) and observational studies published until April 2020 on walnut intake, cognition (e.g. cognitive function, stroke, and mood), and selected risk factors for cognitive decline (e.g. glucose homeostasis and inflammation). Risk-of-bias and strength-of-evidence assessments were conducted using standard validated tools. Random-effects meta-analyses were conducted when ≥3 studies reported quantitative data for each outcome. Results: 32 RCT and 7 observational study publications were included. Meta-analysis of cognition-related outcomes could not be conducted due to heterogeneity of tests. None of the 5 cognition RCTs found significant effects of walnuts on overall cognition, although 3 studies found improvements on subdomains and/or subgroups. All 7 observational studies found significant associations and a dose-response relationship between walnut intake and cognition-related outcomes. Meta-analyses of 27 RCTs reporting glucose homeostasis and inflammation outcomes, selected risk factors for cognitive decline, did not show significant effects of walnut intake. Conclusions: Due to the non-uniformity of tests for cognition-related outcomes, definitive conclusions regarding the effect of walnut consumption on cognition could not be reached. Additionally, evidence does not show associations between walnut intake and glucose homeostasis or inflammation, cognitive decline risk-factors. High-quality studies with standardized measures are needed to clarify the role of walnuts in cognitive health.

Effects of daily almond consumption for six months on cognitive measures in healthy middle-aged to older adults: a randomized control trial.

Rakic, J.M., J. Tanprasertsuk, T.M. Scott, H.M. Rasmussen, E.S. Mohn, C.-Y.O. Chen, E.J. Johnson, 2021. Effects of daily almond consumption for six months on cognitive measures in healthy middle-aged to older adults: a randomized control trial. Nutr Neurosci. 1-11.  doi: 10.1080/1028415X.2020.1868805.

Background: Age-related cognitive decline is a major public health issue. Almonds are rich in nutrients that benefit cognitive function. Objective: To investigate the impact of almonds on cognition in elderly adults. Design: In a six-month, single-blinded, randomized-controlled trial, the effects of an almond intervention on cognition in healthy, middle-aged/older adults (50-75 years) was tested. Subjects were assigned to one of three groups: 1.5 oz/d almond (n = 19), 3 oz/d almond (n = 24), or 3.5 oz/d snack (control, matched for macronutrients in 3.0 oz almonds, (n = 17). Serum analyses for tocopherols, oxidative status and inflammation, and cognition were assessed at baseline (M0), three (M3), and six (M6) months. Results: At M6, serum alpha-tocopherol concentrations increased by 8% from M0 (p < 0.05) in the 3 oz almond group but did not increase in the other groups. Serum markers of inflammation and oxidative stress were not significantly different throughout the study among the groups. There was no difference in change over time in cognitive tests among the groups. However, there was a significant improvement in visuospatial working memory (p = 0.023), visual memory and learning (p = 0.017), and spatial planning and working memory (p < 0.001) in subjects receiving 3 oz/d almonds at M6, while the snack group showed no improvement. Conclusions: Almonds did not significantly improve cognitive function in cognitively intact middle-aged/older adults over six months. However, a significant improvement at M6 in cognitive measures was observed with 3 oz/d almonds. While these results are encouraging, a study of longer duration in subjects at risk for age-related cognitive decline is warranted. 

Nut consumption for cognitive performance: A systematic review.

Theodore, L.E., N.J. Kellow, E.A. McNeil, E.O. Close, E.G. Coad, B.R. Cardoso, 2020. Nut consumption for cognitive performance: A systematic review. Adv Nutr. 00:1–16.

Diet is considered an important modifiable lifestyle factor capable of attenuating early cognitive changes in healthy older people. The inclusion of nuts in the diet has been investigated as a dietary strategy for maintenance of brain health across the lifespan. This review aimed to present up-to-date evidence regarding the association between nut intake and cognitive performance. Four databases (Ovid MEDLINE, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, and Embase) were systematically searched from inception to April 2020. Eligible articles were interventional or observational studies in humans aged ≥18 y that measured the effects (or association) of nuts (almond, hazelnut, macadamia, pistachio, walnut, pecan, pine nut, Brazil nut, cashew, peanut) on cognitive outcomes. Out of the 2374 articles identified in the searches, 22 involving 43,793 participants met the criteria and were ultimately included in this review. Memory (immediate and delayed), attention, processing speed, executive function, and visual-spatial ability, as well as risk of mild cognitive impairment, were the outcomes investigated. Lack of consistency across the studies regarding study design, types of nut used, and cognitive outcomes measured resulted in inconsistent evidence that the regular consumption of mixed nuts has a protective effect on cognition in adults of different ages. Nonetheless, we observed that studies targeting populations with a higher risk of cognitive decline tended to find a more favorable outcome. Furthermore, homogeneous findings were observed in the studies that specifically addressed the association between walnut consumption and cognitive performance: out of the 6 studies, including 2 randomized controlled trials, only 1 did not find a positive association.

A walnut diet in combination with enriched environment improves cognitive function and affects lipid metabolites in brain and liver of aged NMRI mice.

Esselun, C., B. Dilberger, C.V. Silaidos, E. Koch, N.H. Schebb, G.P. Eckert, 2020. A walnut diet in combination with enriched environment improves cognitive function and affects lipid metabolites in brain and liver of aged NMRI mice. Neuromolecular Med. doi:10.1007/s12017-020-08639-7.

This in vivo study aimed to test if a diet enriched with 6% walnuts alone or in combination with physical activity supports healthy ageing by changing the oxylipin profile in brain and liver, improving motor function, cognition, and cerebral mitochondrial function. Female NMRI mice were fed a 6% walnut diet starting at an age of 12 months for 24 weeks. One group was additionally maintained in an enriched environment, one group without intervention served as control. After three months, one additional control group of young mice (3 weeks old) was introduced. Motor and cognitive functions were measured using Open Field, Y-Maze, Rotarod and Passive Avoidance tests. Lipid metabolite profiles were determined using RP-LC-ESI(-)-MS/MS in brain and liver tissues of mice. Cerebral mitochondrial function was characterized by the determination of ATP levels, mitochondrial membrane potential and mitochondrial respiration. Expression of genes involved with mito- and neurogenesis, inflammation, and synaptic plasticity were determined using qRT-PCR. A 6% walnut-enriched diet alone improved spatial memory in a Y-Maze alternation test (p < 0.05) in mice. Additional physical enrichment enhanced the significance, although the overall benefit was virtually identical. Instead, physical enrichment improved motor performance in a Rotarod experiment (p* < 0.05) which was unaffected by walnuts alone. Bioactive oxylipins like hydroxy-polyunsaturated fatty acids (OH-PUFA) derived from linoleic acid (LA) were significantly increased in brain (p** < 0.01) and liver (p*** < 0.0001) compared to control mice, while OH-PUFA of α-linolenic acid (ALA) could only be detected in the brains of mice fed with walnuts. In the brain, walnuts combined with physical activity reduced arachidonic acid (ARA)-based oxylipin levels (p < 0.05). Effects of walnut lipids were not linked to mitochondrial function, as ATP production, mitochondrial membrane potential and mitochondrial respiration were unaffected. Furthermore, common markers for synaptic plasticity and neuronal growth, key genes in the regulation of cytoprotective response to oxidative stress and neuronal growth were unaffected. Taken together, walnuts change the oxylipin profile in liver and brain, which could have beneficial effects for healthy ageing, an effect that can be further enhanced with an active lifestyle. Further studies may focus on specific nutrient lipids that potentially provide preventive effects in the brain.

Bishop, N., K. Zuniga, 2020. Investigating walnut consumption and cognitive trajectories in a representative sample of older US adults.

Bishop, N., K. Zuniga, 2020. Investigating walnut consumption and cognitive trajectories in a representative sample of older US adults. Public Health Nutrition, 1-12. doi:10.1017/S1368980020001287

Objective: Existing research suggests walnut intake may be associated with better cognitive function in older adults, yet few studies utilise longitudinal data from observational studies of ageing populations. Our objective was to estimate the association between whole walnut intake and cognitive change in a representative sample of older Americans. Design: Secondary analysis of the Health and Retirement Study and Health Care and Nutrition Study. Walnut consumption was defined as a categorical measure (none, low intake (0·01–0·08 1 oz. servings per day) and moderate intake (>0·08 1 oz. servings per day)) and cognitive function was measured using the Telephone Interview for Cognitive Status. Latent growth modelling estimated the association between walnut consumption and trajectories of cognitive status over a 4-year observational period. Sensitivity analyses assessing non-random dropout and Monte Carlo power analyses were conducted to contextualise results. Setting: The USA. Participants: A sample of 3632 US adults aged 65 years and older. Results: Those reporting any walnut consumption had greater cognitive scores at baseline than those not consuming walnuts (low walnut consumption, b = 1·53, se = 0·21, P < 0·001; moderate walnut consumption, b = 2·22, se = 0·27, P < 0·001), but walnut consumption was not associated with cognitive change. Walnut consumption was positively associated with socioeconomic status and health behaviours as well as intake of nutrients identified to have neuroprotective benefits. Conclusions: We identified an association between walnut consumption and cognitive function in older adults, although we did not find that walnut consumption was protective against age-related cognitive decline.

Consumption of dietary nuts in midlife and risk of cognitive impairment in late-life: the Singapore Chinese Health Study.

Jiang, Y.W., L.-T. Sheng L. Feng, A. Pan, W.-P. Koh, 2020. Consumption of dietary nuts in midlife and risk of cognitive impairment in late-life: the Singapore Chinese Health Study. Age and Ageing. 1–7 doi: 10.1093/ageing/afaa267.

Background: evidence from prospective studies investigating the association between consumption of nuts in midlife and risk of cognitive impairment in late life is limited. Methods: this study analysed data from 16,737 participants in a population-based cohort, the Singapore Chinese Health Study. Intake of nuts was assessed using a validated food-frequency questionnaire at baseline (1993–1998), when participants were 45–74 years old (mean age = 53.5 years). Cognitive function was tested using the Singapore modified Mini-Mental State Examination during the third follow-up visit (2014–2016), when participants were 61–96 years old (mean age = 73.2 years). Cognitive impairment was defined using education-specific cut-off points. Logistic regression models were used to estimate the odds ratio (OR) and the 95% confidence interval (CI) for the association between intake and risk of cognitive impairment. Results: cognitive impairment was identified in 2,397 (14.3%) participants. Compared with those who consumed < 0.001). Conclusion: higher intake of nuts in midlife was related to a lower risk of cognitive impairment in late life, which was partly mediated by unsaturated fatty acids.

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

Sala-Vila, A., C. Valls-Pedret, S. Rajaram, N. Coll-Padrós, M. Cofán, M. Serra-Mir, A.M. Pérez-Heras, I. Roth, T.M. Freitas-Simoes, M. Doménech, C. Calvo, A. López-Illamola, E. Bitok, N.K. Buxton, L. Huey, A. Arechiga, K. Oda, G.J. Lee, D. Corella, L. Vaqué-Alcázar, R. Sala-Llonch, D. Bartrés-Faz, J. Sabaté, E. Ro, 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. pii: nqz328. doi: 10.1093/ajcn/nqz328. [Epub ahead of print]

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.

Consumption of Nuts at Midlife and Healthy Aging in Women.

Freitas-Simoes, T.M., M. Wagner, C. Samieri, A. Sala-Vila, F. Grodstein, 2020. Consumption of Nuts at Midlife and Healthy Aging in Women. J Aging Res. https://doi.org/10.1155/2020/5651737.

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, P 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 (P 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.

Walnut-associated fatty acids inhibit LPS-induced activation of BV-2 microglia.

Carey, A.N., D.R. Fisher, D.F. Bielinski, D.S. Cahoon, B. Shukitt-Hale, 2020. Walnut-associated fatty acids inhibit LPS-induced activation of BV-2 microglia. Inflammation. 43(1):241-250.

Walnuts have high levels of the omega-3 fatty acid alpha-linolenic acid (C18:3n-3, ALA) and the omega-6 fatty acid linoleic acid (C18:2n-6, LA). Previous research has demonstrated that pre-treatment of BV-2 microglia with walnut extract inhibited lipopolysaccharide (LPS)-induced activation of microglia. As an extension of that study, the effects of walnut-associated fatty acids on BV-2 microglia were assessed. BV-2 murine microglia cells were treated with LA, ALA, or a combination of LA+ALA prior to or after exposure to LPS. Nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) were measured in cell-conditioned media. Cyclooxeganse-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression were assessed in BV-2 microglia. Both LA and ALA protected against LPS-induced increases in NO, iNOS, COX-2, and TNF-alpha when used before LPS exposure. When BV-2 microglia were treated with fatty acids after LPS, only COX-2 and TNF-alpha were significantly attenuated by the fatty acids. There was no synergism of LA+ALA, as the LA+ALA combination was no more effective than LA or ALA alone. Fatty acids, like those found in walnuts, may protect against production of cytotoxic intermediates and cell-signaling molecules from microglia and may prove beneficial for preventing age- or disease-related neurodegeneration.