Research Area: Cognitive Health

Bell, L., G.F. Dodd, M. Jeavons, D.R. Fisher, A.R. Whyte, B. Shukitt-Hale, C.M. Williams, 2025. The impact of a walnut-rich breakfast on cognitive performance and brain activity throughout the day in healthy young adults: a crossover intervention trial. Food Funct. 16(5):1696-1707. https://doi.org/10.1039/d4fo04832f

A healthy diet is essential for optimal brain health and many bioactives from food are linked to cognitive benefits. To examine whether walnuts led to cognitive improvements throughout the day, 32 healthy young adults, aged 18-30, were tested in a double-blind, crossover pilot study, to compare the effects of a breakfast containing 50 g walnuts with a calorie-matched control containing no nuts. Cognition, mood, blood, and EEG measures were recorded at baseline and 2, 4, and 6 hours postprandially. Mood ratings for negative affect appeared worse following walnuts compared to control, possibly due to a general dislike of the intervention. However, walnuts elicited faster reaction times throughout the day on executive function tasks. Memory recall performance at 2 hours was worse for walnuts compared to control, but by 6 hours this finding was reversed with walnuts outperforming the control. EEG PSD analysis revealed differences in frontoparietal activity in the walnut condition compared to the control condition during memory recall and during executive function performance. These results may reflect between-treatment differences in cognitive effort or attentional processes while performing the tasks. Blood analysis revealed lower circulating non-esterified fatty acids and small increases in glucose availability following consumption of walnuts compared to control, suggesting enhanced glucose availability as one possible mechanism of action. Further investigations of other potential mechanisms are needed. Overall, these findings provide evidence for reaction time benefits throughout the day following a walnut-rich breakfast, while memory findings were mixed with benefits only observed later in the day. However, more research is needed into how diets containing walnuts might regulate cognitive improvements in humans postprandially and over the longer term.

Lázaro, I., O. Grau-Rivera, M. Suárez-Calvet, K. Fauria, C. Minguillón, M. Shekari, C. Falcón, M. García-Prat, J. Huguet, J.L. Molinuevo, J.D. Gispert, A. Sala-Vila, 2024. Omega-3 blood biomarkers relate to brain glucose uptake in individuals at risk of Alzheimer’s disease dementia. Alzheimers Dement (Amst). 16(3):e12596. https://doi.org/10.1002/dad2.12596

Introduction: Brain glucose hypometabolism is a preclinical feature of Alzheimer’s disease (AD). Dietary omega-3 fatty acids promote brain glucose metabolism, but clinical research is incipient. Circulating omega-3s objectively reflect their dietary intake. Methods: This was a cross-sectional study in 320 cognitively unimpaired participants at increased risk of AD dementia. Using lipidomics, we determined blood docosahexaenoic (DHA) and alpha-linolenic (ALA) acid levels (omega-3s from marine and plant origin, respectively). We assessed brain glucose metabolism using [18-F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). Results: Blood ALA directly related to FDG uptake in brain areas known to be affected in AD. Stronger associations were observed in apolipoprotein E ε4 carriers and homozygotes. For DHA, significant direct associations were restricted to amyloid beta-positive tau-positive participants. Discussion: Blood omega-3 directly relate to preserved glucose metabolism in AD-vulnerable brain regions in individuals at increased risk of AD dementia. This adds to the benefits of omega-3 supplementation in the preclinical stage of AD dementia. Highlights: Blood omega-3s were related to brain glucose uptake in participants at risk of Alzheimer’s disease (AD) dementia. Complementary associations were observed for omega-3 from marine and plant sources. Foods rich in omega-3 might be useful in early features of AD.

Ayala-Aldana, N., A. Pinar-Martí, M. Ruiz-Rivera, S. Fernández-Barrés, D. Romaguera, J. Casanova-Mollà, N. Solà-Valls, J. Julvez, 2024. Original article: adolescent dietary patterns derived using principal component analysis and neuropsychological functions: a cross-sectional analysis of Walnuts Smart Snack cohort. Eur Child Adolesc Psychiatry. 2024 Sep 18. https://doi.org/10.1007/s00787-024-02577-6

A balanced diet is relevant for neuropsychological functioning. We aimed to analyze the association between dietary patterns and neuropsychological outcomes in a sample of healthy adolescents of the Walnuts Smart Snack (WSS) cohort from Barcelona city. We performed principal components analysis (PCA) to determine dietary patterns in the adolescent sample using a food frequency questionnaire (60 items). Multiple linear regression models were performed to analyze the association between PCA dietary patterns with neuropsychological outcomes: Strengths and Difficulties (SDQ) externalizing and internalizing scores, Attention Network Test (ANT) Impulsivity Index and Emotional Recognition Task (ERT) scores. We additionally adjusted the models for child sex, age, body mass index (BMI), physical activity and maternal education. Six dietary patterns were identified in PCA analyses. “low consumption of calorie-dense foods” dietary pattern had a negative association (protective) with the both SDQ outcomes (p value < 0.001) and “Nuts” dietary pattern showed a negative (protective) association with impulsivity index (β1= −24.60, 95% CI = −36.80, −12.41, p value < 0.001). Overall, our main results suggest that healthy dietary patterns, including higher intakes of “nuts” and a preference of “low consumption of calorie-dense foods” dietary patterns, could provide a beneficial association with neuropsychological functions during the adolescence period. The associations may include improvements of externalizing and internalizing problem symptoms, and impulsivity.

Novaj, A., M.G. Engel, R. Wang, K. Mao, X. Xue, Y. Amir, G. Atzmon, D.M. Huffman, 2023. Dietary walnuts preserve aspects of health span and alter the hippocampal lipidome in aged high-fat diet-fed mice. Int. J. Mol. Sci. 24(3), 2314. https://doi.org/10.3390/ijms24032314

Evidence continues to accrue that aging and its diseases can be delayed by pharmacologic and dietary strategies that target the underlying hallmarks of the aging process. However, identifying simple, safe, and effective dietary strategies involving the incorporation of whole foods that may confer some protection against the aging process is also needed. Recent observational studies have suggested that nut consumption can reduce mortality risk in humans. Among these, walnuts are particularly intriguing, given their high content of n-3 fatty acids, fiber, and antioxidant and anti-inflammatory compounds. To this end, 12-month-old male CB6F1 mice were provided either a defined control low-fat diet (LFD), a control high-fat diet (HFD), or an isocaloric HFD containing 7.67% walnuts by weight (HFD + W), and measures of health span and related biochemical markers (n = 10-19 per group) as well as survival (n = 20 per group) were monitored. Mice provided the HFD or HFD + W demonstrated marked weight gain, but walnuts lowered baseline glucose (p < 0.05) and tended to temper the effects of HFD on liver weight gain (p < 0.05) and insulin tolerance (p = 0.1). Additional assays suggested a beneficial effect on some indicators of health with walnut supplementation, including preservation of exercise capacity and improved short-term working memory, as determined by Y maze (p = 0.02). However, no effect was observed via any diet on inflammatory markers, antioxidant capacity, or survival (p = 0.2). Ingenuity Pathway Analysis of the hippocampal transcriptome identified two processes predicted to be affected by walnuts and potentially linked to cognitive function, including estrogen signaling and lipid metabolism, with changes in the latter confirmed by lipidomic analysis. In summary, while walnuts did not significantly improve survival on a HFD, they tended to preserve features of health span in the context of a metabolic stressor with aging.

Pinar-Martí, A., F. Gignac, S. Fernández-Barrés, D. Romaguera, A. Sala-Vila, I. Lázaro, O.T. Ranzani, C. Persavento, A. Delgado, A. Carol, J. Torrent, J. Gonzalez, E. Roso, J. Barrera-Gómez, M. López-Vicente, O. Boucher, M. Nieuwenhuijsen, M.C. Turner, M. Burgaleta, J. Canals,  V. Arija, X. Basagaña , E. Ros, J. Salas-Salvadó , J. Sunyer, J. Julvez, 2023. Effect of walnut consumption on neuropsychological development in healthy adolescents: a multi-school randomised controlled trial. EClinicalMedicine. 59, 101954. https://doi.org/10.1016/j.eclinm.2023.101954

Background: Omega-3 fatty acids are critical for neuropsychological functioning. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. The potential benefit on adolescent neurodevelopment of consuming walnuts, a source of omega-3 alpha-linolenic acid (ALA), remains unclear. Methods: We conducted a 6-month multi-school-based randomized controlled nutrition intervention trial to assess whether walnut consumption has beneficial effects on the neuropsychological and behavioral development of adolescents. The study took place between 04/01/2016 and 06/30/2017 in twelve different high schools in Barcelona, Spain (ClinicalTrials.gov Identifier: NCT02590848). A total of 771 healthy teenagers aged 11–16 years were randomized into two equal groups (intervention or control). The intervention group received 30 g/day of raw walnut kernels to be incorporated into their diet for 6 months. Multiple primary endpoints concerning neuropsychological (working memory, attention, fluid intelligence, and executive function) and behavioral (socioemotional and attention deficit hyperactivity disorder [ADHD] symptoms) development were assessed at baseline and after intervention. Red blood cell (RBC) ALA status was determined at baseline and 6 months as a measure of compliance. Main analyses were based on intention-to-treat using a linear mixed-effects model. A per-protocol effect of the intervention was analysed using inverse-probability weighting to account for post-randomization prognostic factors (including adherence) using generalized estimating equations. Findings: In intention-to-treat analyses, at 6 months there were no statistically significant changes between the intervention and control groups for all primary endpoints. RBC ALA (%) significantly increased only in the intervention group, coefficient = 0.04 (95% Confidence Interval (CI) = 0.03, 0.06; p < 0.0001). The per-protocol (adherence-adjusted) effect on improvement in attention score (hit reaction time variability) was −11.26 ms (95% CI = −19.92, −2.60; p = 0.011) for the intervention group as compared to the control group, improvement in fluid intelligence score was 1.78 (95% CI = 0.90, 2.67; p < 0.0001), and reduction of ADHD symptom score was −2.18 (95% CI = −3.70, −0.67; p = 0.0050). Interpretation Our study suggested that being prescribed eating walnuts for 6 months did not improve the neuropsychological function of healthy adolescents. However, improved sustained attention, fluid intelligence, and ADHD symptoms were observed in participants who better complied with the walnut intervention. This study provides a foundation for further clinical and epidemiological research on the effect of walnuts and ALA on neurodevelopment in adolescents.

Pinar-Martí, A., S. Fernández-Barrés, F. Gignac, C. Persavento, A. Delgado, D. Romaguera, I. Lázaro, E. Ros, M. López-Vicente, J. Salas-Salvadó, A. Sala-Vila, J. Júlvez, 2023. Red blood cell omega-3 fatty acids and attention scores in healthy adolescents. Eur. Child Adolesc. Psychiatry. 32(11):2187–2195. https://doi.org/10.1007/s00787-022-02064-w

Omega-3 fatty acids are critical for brain function. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. In contrast to the abundant research on the omega-3 docosahexaenoic acid (DHA) in cognition, research on DHA and attention in healthy adolescents is scarce. In addition, the role of alpha-linolenic acid (ALA), the vegetable omega-3 fatty acid, is unexplored. We examined associations between DHA and ALA and attention function among a healthy young population. In this cross-sectional study conducted in 372 adolescents (13.8±0.9 years-old), we determined the red blood cell proportions of DHA and ALA by gas chromatography (objective biomarkers of their long-term dietary intake) and measured attention scores through the Attention Network Test. We constructed multivariable linear regression models to analyze associations, controlling for known confounders. Compared to participants at the lowest DHA tertile (reference), those at the highest DHA tertile showed significantly lower hit reaction time-standard error (higher attentiveness) (28.13 ms, 95% confidence interval [CI]= – 52.30; – 3.97), lower hit reaction time ( – 38.30 ms, 95% CI= – 73.28; – 3.33) and lower executive conflict response ( – 5.77 ms, 95% CI= – 11.44; – 0.09). In contrast, higher values were observed in those at the top tertile of ALA in hit reaction time compared to the lowest one (46.14 ms, 95% CI=9.90; 82.34). However, a beneficial association was observed for ALA, with decreasing impulsivity index across tertiles. Overall, our results suggest that DHA (reflecting its dietary intake) is associated with attention performance in typically developing adolescents. The role of dietary ALA in attention is less clear, although higher blood levels of ALA appear to result in lower impulsivity. Future intervention studies are needed to determine the causality of these associations and to better shape dietary recommendations for brain health during the adolescence period.