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Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial. LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705. Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was −0·028 (SD 0·453) in the active group and −0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI −0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of −0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention. The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed. European Commission 7th Framework Programme.

Dietary components are essential for the structural and functional development of the brain. Among these, docosahexaenoic acid, 22:6n-3 (DHA), is critically necessary for the structure and development of the growing fetal brain in utero. DHA is the major n-3 long-chain polyunsaturated fatty acid in brain gray matter representing about 15% of all fatty acids in the human frontal cortex. DHA affects neurogenesis, neurotransmitter, synaptic plasticity and transmission, and signal transduction in the brain. Data from human and animal studies suggest that adequate levels of DHA in neural membranes are required for maturation of cortical astrocyte, neurovascular coupling, and glucose uptake and metabolism. Besides, some metabolites of DHA protect from oxidative tissue injury and stress in the brain. A low DHA level in the brain results in behavioral changes and is associated with learning difficulties and dementia. In humans, the third trimester-placental supply of maternal DHA to the growing fetus is critically important as the growing brain obligatory requires DHA during this window period. Besides, DHA is also involved in the early placentation process, essential for placental development. This underscores the importance of maternal intake of DHA for the structural and functional development of the brain. This review describes DHA’s multiple roles during gestation, lactation, and the consequences of its lower intake during pregnancy and postnatally on the 2019 brain development and function.

Microalgae offer a promising sustainable source of essential nutrients, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). DHA and EPA are mainly obtained through fish, which are limited in number due to global climate change. Microalgal oil, on the other hand, has emerged as a sustainable and limitless source of DHA and EPA but the bioavailability of these nutrients has not been directly compared to fish oil. Therefore, the objective of this study is to evaluate and demonstrate the comparable DHA and EPA plasma bioavailability of microalgal and fish oil. We analyzed the plasma phospholipid levels of 74 adult men and women after 6 and 14 weeks of consuming omega-3 supplements derived from either microalgal or fish oil in a randomized double-blind placebo-controlled parallel-group clinical trial. We found that the bioavailability of DHA and EPA in plasma phospholipids from microalgal oil supplements are statistically non-inferior compared to fish oil supplements, despite the differences in production process and composition, indicating that microalgal oil is a reliable and bioavailable source of DHA and EPA.

The purpose of the present study is to investigate the effects of krill oil and fish oil on serum lipids and markers of oxidative stress and inflammation and to evaluate if different molecular forms, triacylglycerol and phospholipids, of omega-3 polyunsaturated fatty acids (PUFAs) influence the plasma level of EPA and DHA differently. One hundred thirteen subjects with normal or slightly elevated total blood cholesterol and/or triglyceride levels were randomized into three groups and given either six capsules of krill oil (N = 36; 3.0 g/day, EPA + DHA = 543 mg) or three capsules of fish oil (N = 40; 1.8 g/day, EPA + DHA = 864 mg) daily for 7 weeks. A third group did not receive any supplementation and served as controls (N = 37). A significant increase in plasma EPA, DHA, and DPA was observed in the subjects supplemented with n-3 PUFAs as compared with the controls, but there were no significant differences in the changes in any of the n-3 PUFAs between the fish oil and the krill oil groups. No statistically significant differences in changes in any of the serum lipids or the markers of oxidative stress and inflammation between the study groups were observed. Krill oil and fish oil thus represent comparable dietary sources of n-3 PUFAs, even if the EPA + DHA dose in the krill oil was 62.8% of that in the fish oil.

Soccer (football) is the most popular sport globally, with 265 million players across all ages and sexes. Repetitive subconcussive head impacts due to heading of the soccer ball can pose threats to healthy brain development and aging. Omega-3 fatty acids, especially docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may have neuroprotective effects, but it remains unclear what aspects of neural health benefit from DHA+EPA when faced with subconcussive head impacts. In a randomized placebo-controlled trial, 208 soccer players will complete baseline measures including demographics, blood sampling, dietary recalls, and psychological assessment. Participants will be randomly assigned to ingest DHA+EPA [3.4g/d: DHA 2.4g+EPA 1.0g] or placebo daily for 8 weeks followed by a subconcussion intervention phase. During the subconcussion intervention, participants will perform a session of 20 controlled soccer headings, with a second session 24 hours later. Blood samples, neuroimaging data, autonomic reactivity, and clinical measures (symptoms, oculomotor, cognition) will be collected pre-heading and 24-hour post-1 st session, 24-hour post-2 nd session, and 7-day post-2 nd session. The primary hypothesis is that DHA+EPA pretreatment will promote neuronal and astrocyte resiliency to subconcussive head impacts, as assessed by blood biomarkers of brain injury, axonal microstructure measured by diffusion tensor imaging, and whole-brain resting-state connectivity. It is proposed that pretreatment will preserve autonomic function, as assessed by the cold pressor test (CPT), as well as oculomotor and cognitive function, even after head impacts. Data from this trial will help clarify the combined effect of DHA+EPA on brain molecular, cellular, and physiological health in response to subconcussive head impacts. If the hypotheses are confirmed, the findings will support a highly practical intervention for mitigating the neurodegenerative cascade triggered by head impacts. Trial registration: ClinicalTrials.gov NCT06736925

Objective Choline and docosahexaenoic acid (DHA) are essential nutrients for preterm infant development. They are metabolically linked via phosphatidylcholine (PC), a constitutive plasma membrane lipid and the major transport form of DHA in plasma. Plasma choline and DHA-PC concentrations rapidly decline after preterm birth. To improve preterm infant nutrition, we evaluated combined compared to exclusive choline and DHA supplementation, and standard feeding. Design Randomized partially blinded single-center trial. Setting Neonatal tertiary referral center in Tübingen, Germany. Patients 24 inborn preterm infants < 32 week postmenstrual age. Interventions Standard nutrition (control) or, additionally, enteral choline (30 mg/kg/day), DHA (60 mg/kg/day), or both for 10 days. Single enteral administration of 3.6 mg/kg [methyl-D 9 -] choline chloride as a tracer at 7.5 days. Main outcome measures Primary outcome variable was plasma choline following 7 days of supplementation. Deuterated and unlabeled choline metabolites, DHA-PC, and other PC species were secondary outcome variables. Results Choline supplementation increased plasma choline to near-fetal concentrations [35.4 (32.8–41.7) µmol/L vs. 17.8 (16.1–22.4) µmol/L, p  < 0.01] and decreased D 9 -choline enrichment of PC. Single DHA treatment decreased DHA in PC relative to total lipid [66 (60–68)% vs. 78 (74–80)%; p  < 0.01], which was prevented by choline. DHA alone increased DHA-PC only by 35 (26–45)%, but combined treatment by 63 (49–74)% ( p  < 0.001). D 9 -choline enrichment showed preferential synthesis of PC containing linoleic acid. PC synthesis via phosphatidylethanolamine methylation resulted in preferential synthesis of DHA-containing D 3 -PC, which was increased by choline supplementation. Conclusions 30 mg/kg/day additional choline supplementation increases plasma choline to near-fetal concentrations, dilutes the D 9 -choline tracer via increased precursor concentrations and improves DHA homeostasis in preterm infants. Trial registration clinicaltrials.gov. Identifier: NCT02509728.

Omega-3 fatty acids are dietary essentials, and the current low intakes in most modern developed countries are believed to contribute to a wide variety of physical and mental health problems. Evidence from clinical trials indicates that dietary supplementation with long-chain omega-3 may improve child behavior and learning, although most previous trials have involved children with neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) or developmental coordination disorder (DCD). Here we investigated whether such benefits might extend to the general child population. To determine the effects of dietary supplementation with the long-chain omega-3 docosahexaenoic acid (DHA) on the reading, working memory, and behavior of healthy schoolchildren. Parallel group, fixed-dose, randomized, double-blind, placebo-controlled trial (RCT). Mainstream primary schools in Oxfordshire, UK (n = 74). Healthy children aged 7-9 years initially underperforming in reading (≤ 33(rd) centile). 1376 invited, 362 met study criteria. 600 mg/day DHA (from algal oil), or taste/color matched corn/soybean oil placebo. Age-standardized measures of reading, working memory, and parent- and teacher-rated behavior. ITT analyses showed no effect of DHA on reading in the full sample, but significant effects in the pre-planned subgroup of 224 children whose initial reading performance was ≤ 20(th) centile (the target population in our original study design). Parent-rated behavior problems (ADHD-type symptoms) were significantly reduced by active treatment, but little or no effects were seen for either teacher-rated behaviour or working memory. DHA supplementation appears to offer a safe and effective way to improve reading and behavior in healthy but underperforming children from mainstream schools. Replication studies are clearly warranted, as such children are known to be at risk of low educational and occupational outcomes in later life. ClinicalTrials.gov NCT01066182 and Controlled-Trials.com ISRCTN99771026.

•In a subsample within VITAL, a double-blind randomized controlled trial of adults randomized to n-3 fatty acids or placebo, we identified reductions in proinflammatory n-3 fatty acid-derived lipid mediators and increases in n-3 fatty acid-derived lipid proresolving mediators in those receiving n-3 fatty acids after 1 y.•Larger 1-y lipid biomarker changes were seen in patients with reported low (<1 serving/mo) vs. high (≥3.9 servings/wk) fish intake at baseline.•Analyses did not reveal significant multiplicative interactions between low vs. high baseline fish intake and randomization to n-3 fatty acids for 1 y upon the change in concentration of lipid mediators. We assessed the joint effects of omega (n)-3 fatty acid supplementation and dietary fish intake on systemic lipid mediators of inflammation among adults. Within VITAL, a double-blind randomized controlled trial, adults were randomized to ω-3 fatty acids (460 mg EPA + 380 mg DHA/d) or placebo. We selected participants who reported low (<1 serving/mo) baseline dietary fish intake and matched them by age, sex, race, and trial arm to participants with self-reported highest fish intake (≥3.9 servings/wk). Baseline and 1-y plasma samples were tested for 9 ω-3 fatty acid-derived lipid mediators. Multivariable linear models assessed lipid mediator changes and joint effects of ω-3 fatty acid supplementation and dietary fish intake. Forty-eight participants with low baseline fish intake were matched to 48 with high fish intake. Mean age was 64.6 (±7.26), 50% were female, and 85% non-Hispanic white. One-year lipid mediator changes in expected directions were observed in those receiving ω-3 fatty acids versus placebo: reductions in proinflammatory mediators, PGD2, 5-HETE, and 12-HETE; increases in proresolving mediators, EPA and DHA. Larger 1-y lipid biomarker changes were seen in those with low baseline fish intake randomized to active ω-3 fatty acids for DHA, EPA, PGD2, Resolvin D1, and Resolvin D4 were observed, although no significant multiplicative interactions were detected. Beneficial changes in circulating proresolving and proinflammatory mediators were found with 1-y of ω-3 fatty acid supplementation versus placebo for all participants, with a trend toward larger effects among those with low baseline fish intake, although interactions were not significant.

Supplementation of omega-3 (n-3) polyunsaturated fatty acids has been associated with reduced side effects and improved quality of life (QoL) in breast cancer patients receiving chemotherapy. The current study reports secondary outcomes from the DHA WIN randomized controlled trial which was designed to evaluate docosahexaenoic acid (DHA) supplementation (4.4 g/day) in conjunction with six cycles of neoadjuvant chemotherapy (NAC) (3 weeks/cycle) in women with non-metastatic breast cancer (n = 49). The objective of the current study was to assess the effects of DHA supplementation on QoL and exercise behaviour in women undergoing NAC for breast cancer. Self-administered questionnaires were used to measure QoL and exercise behaviour before starting chemotherapy (baseline), before each chemotherapy cycle (exercise), and after completing chemotherapy. DHA supplementation did not significantly affect QoL, aerobic exercise volume or resistance training frequency during treatment. However, mean aerobic exercise volume was significantly lower at week 12 (-53.5 minutes/week; 95% CI, -100.5 to -6.3; p = 0.02) and week 18 (-70.8 minutes/week; 95% CI, -123.0 to -18.6; p = 0.01) compared to baseline. Mean resistance training frequency was lower at week 12 (-0.57 times/week; 95% CI, -1.0 to -0.13; p = 0.02) compared to baseline. Meeting exercise guidelines during chemotherapy was not associated with better QoL. In the current exploratory study, QoL and exercise decreased during treatment regardless of DHA supplementation, highlighting the need for supportive care and potential therapies that may mitigate these declines in breast cancer patients receiving NAC. Adequately powered studies are needed to determine if DHA supplementation improves these two indices of health. The trial is registered at ClinicalTrials.gov (NCT03831178).

Specialized pro-resolving mediator(s) (SPMs) are produced from the endogenous ω-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and accelerate resolution of acute inflammation. We identified specific clusters of SPM in human plasma and serum using LC-MS/MS based lipid mediator (LM) metabololipidomics in two separate laboratories for inter-laboratory validation. The human plasma cluster consisted of resolvin (Rv)E1, RvD1, lipoxin (LX)B 4 , 18-HEPE, and 17-HDHA, and the human serum cluster consisted of RvE1, RvD1, AT-LXA 4 , 18-HEPE, and 17-HDHA. Human plasma and serum SPM clusters were increased after ω-3 supplementation (triglyceride dietary supplements or prescription ethyl esters) and low dose intravenous lipopolysaccharide (LPS) challenge. These results were corroborated by parallel determinations with the same coded samples in a second, separate laboratory using essentially identical metabololipidomic operational parameters. In these healthy subjects, two ω-3 supplementation protocols (Study A and Study B) temporally increased the SPM cluster throughout the endotoxin-challenge time course. Study A and Study B were randomized and Study B also had a crossover design with placebo and endotoxin challenge. Endotoxin challenge temporally regulated lipid mediator production in human serum, where pro-inflammatory eicosanoid (prostaglandins and thromboxane) concentrations peaked by 8 hours post-endotoxin and SPMs such as resolvins and lipoxins initially decreased by 2 h and were then elevated at 24 hours. In healthy adults given ω-3 supplementation, the plasma concentration of the SPM cluster (RvE1, RvD1, LXB 4 , 18-HEPE, and 17-HDHA) peaked at two hours post endotoxin challenge. These results from two separate laboratories with the same samples provide evidence for temporal production of specific pro-resolving mediators with ω-3 supplementation that together support the role of SPM in vivo in inflammation-resolution in humans.