Kinetics of 13C-DHA before and during fish-oil supplementation in healthy older individuals

Background: Docosahexaenoic acid (DHA) kinetics appear to change with intake, which is an effect that we studied in an older population by using uniformly carbon-13–labeled DHA (13C-DHA). Objective: We evaluated the influence of a fish-oil supplement over 5 mo on the kinetics of 13C-DHA in older persons. Design: Thirty-four healthy, cognitively normal participants (12 men, 22 women) aged between 52 and 90 y were recruited. Two identical kinetic studies were performed, each with the use of a single oral dose of 40 mg 13C-DHA. The first kinetic study was performed before participants started taking a 5-mo supplementation that provided 1.4 g DHA/d plus 1.8 g eicosapentaenoic acid (EPA)/d (baseline); the second study was performed during the final month of supplementation (supplement). In both kinetic studies, blood and breath samples were collected ≤8 h and weekly over 4 wk to analyze 13C enrichment. Results: The time × supplement interaction for 13C-DHA in the plasma was not significant, but there were separate time and supplement effects (P < 0.0001). The area under the curve for plasma 13C-DHA was 60% lower while subjects were taking the supplement than at baseline (P < 0.0001). The uniformly carbon-13–labeled EPA concentration was 2.6 times as high 1 d posttracer while patients were taking the supplement as it was at baseline. The mean (±SEM) plasma 13C-DHA half-life was 4.5 ± 0.4 d at baseline compared with 3.0 ± 0.2 d while taking the supplement (P < 0.0001). Compared with baseline, the mean whole-body half-life was 61% lower while subjects were taking the supplement. The loss of 13C-DHA through β-oxidation to carbon dioxide labeled with carbon-13 increased from 0.085% of dose/h at baseline to 0.208% of dose/h while subjects were taking the supplement. Conclusions: In older persons, a supplement of 3.2 g EPA + DHA/d increased β-oxidation of 13C-DHA and shortened the plasma 13C-DHA half-life. Therefore, when circulating concentrations of EPA and DHA are increased, more DHA is available for β-oxidation. This trial was registered at clinicaltrials.gov as NCT01577004

Alzheimer\u27s Therapeutics Targeting Amyloid Beta 1-42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors is Displaced by Drug Candidates That Improve Cognitive Deficits

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer\u27s disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer\u27s disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer\u27s therapeutics

DHA Supplemented in Peptamen Diet Offers No Advantage in Pathways to Amyloidosis: Is It Time to Evaluate Composite Lipid Diet?

Numerous reports have documented the beneficial effects of dietary docosahexaenoic acid (DHA) on beta-amyloid production and Alzheimer's disease (AD). However, none of these studies have examined and compared DHA, in combination with other dietary nutrients, for its effects on plaque pathogenesis. Potential interactions of DHA with other dietary nutrients and fatty acids are conventionally ignored. Here we investigated DHA with two dietary regimes; peptamen (pep+DHA) and low fat diet (low fat+DHA). Peptamen base liquid diet is a standard sole-source nutrition for patients with gastrointestinal dysfunction. Here we demonstrate that a robust AD transgenic mouse model shows an increased tendency to produce beta-amyloid peptides and amyloid plaques when fed a pep+DHA diet. The increase in beta-amyloid peptides was due to an elevated trend in the levels of beta-secretase amyloid precursor protein (APP) cleaving enzyme (BACE), the proteolytic C-terminal fragment beta of APP and reduced levels of insulin degrading enzyme that endoproteolyse beta-amyloid. On the contrary, TgCRND8 mice on low fat+DHA diet (based on an approximately 18% reduction of fat intake) ameliorate the production of abeta peptides and consequently amyloid plaques. Our work not only demonstrates that DHA when taken with peptamen may have a tendency to confer a detrimental affect on the amyloid plaque build up but also reinforces the importance of studying composite lipids or nutrients rather than single lipids or nutrients for their effects on pathways important to plaque development

Exploring the association between Alzheimer’s disease, oral health, microbial endocrinology and nutrition

Longitudinal monitoring of patients suggests a causal link between chronic periodontitis and the development of Alzheimer’s disease (AD). However, the explanation of how periodontitis can lead to dementia remains unclear. A working hypothesis links extrinsic inflammation as a secondary cause of AD. This hypothesis suggests a compromised oral hygiene leads to a dysbiotic oral microbiome whereby Porphyromonas gingivalis, a keystone periodontal pathogen, with its companion species, orchestrates immune subversion in the host. Brushing and chewing on teeth supported by already injured soft tissues leads to bacteraemias. As a result, a persistent systemic inflammatory response develops to periodontal pathogens. The pathogens, and the host’s inflammatory response, subsequently lead to the initiation and progression of multiple metabolic and inflammatory co-morbidities, including AD. Insufficient levels of essential micronutrients can lead to microbial dysbiosis through the growth of periodontal pathogens such as demonstrated for P. gingivalis under low hemin bioavailability. An individual’s diet also defines the consortium of microbial communities that take up residency in the oral and gastrointestinal (GI) tract microbiomes. Their imbalance can lead to behavioural changes. For example, probiotics enriched in Lactobacillus genus of bacteria, when ingested, exert some anti-inflammatory influence through common host/bacterial neurochemicals, both locally, and through sensory signalling back to the brain. Early life dietary behaviours may cause an imbalance in the host/microbial endocrinology through a dietary intake incompatible with a healthy GI tract microbiome later in life. This imbalance in host/microbial endocrinology may have a lasting impact on mental health. This observation opens up an opportunity to explore the mechanisms, which may underlie the previously detected relationship between diet, oral/GI microbial communities, to anxiety, cognition and sleep patterns. This review suggests healthy diet based interventions that together with improved life style/behavioural changes may reduce and/or delay the incidence of AD

Interplay between n-3 and n-6 long-chain polyunsaturated fatty acids and the endocannabinoid system in brain protection and repair.

The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFA) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA) have shown beneficial effects on learning and memory, neuroinflammatory processes and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-archidonoylglycerol (2-AG) are the most widely studied endocannabinoids, and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair

Nutrition and the ageing brain: moving towards clinical applications

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

Nutrition for the ageing brain: towards evidence for an optimal diet

As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline

The older people, omega-3, and cognitive health (EPOCH) trial design and methodology: A randomised, double-blind, controlled trial investigating the effect of long-chain omega-3 fatty acids on cognitive ageing and wellbeing in cognitively healthy older adults

Extent: 18p.Background: Some studies have suggested an association between omega-3 long-chain polyunsaturated fatty acids (n-3 LC PUFAs) and better cognitive outcomes in older adults. To date, only two randomised, controlled trials have assessed the effect of n-3 LC PUFA supplementation on cognitive function in older cognitively healthy populations. Of these trials only one found a benefit, in the subgroup carrying the ApoE-ε4 allele. The benefits of n-3 LC PUFA supplementation on cognitive function in older normal populations thus still remain unclear. The main objective of the current study was to provide a comprehensive assessment of the potential of n-3 LC PUFAs to slow cognitive decline in normal elderly people, and included ApoE-ε4 allele carriage as a potential moderating factor. The detailed methodology of the trial is reported herein. Methods: The study was a parallel, 18-month, randomised, double-blind, placebo-controlled intervention with assessment at baseline and repeated 6-monthly. Participants (N = 391, 53.7% female) aged 65-90 years, English-speaking and with normal cognitive function, were recruited from metropolitan Adelaide, South Australia. Participants in the intervention arm received capsules containing fish-oil at a daily dosage of 1720 mg of docosahexaenoic acid and 600 mg of eicosapentaenoic acid while the placebo arm received the equivalent amount of olive oil in their capsules. The primary outcome is rate of change in cognitive performance, as measured by latent variables for the cognitive constructs (encompassing Reasoning, Working Memory, Short-term Memory, Retrieval Fluency, Inhibition, Simple and Choice-Reaction Time, Perceptual Speed, Odd-man-out Reaction Time, Speed of Memory Scanning, and Psychomotor Speed) and assessed by latent growth curve modeling. Secondary outcomes are change in the Mini-mental State Examination, functional capacity and well-being (including health status, depression, mood, and self-report cognitive functioning), blood pressure, and biomarkers of n-3 LC PUFA status, glucose, lipid metabolism, inflammation, oxidative stress, and DNA damage.Vanessa Danthiir, Nicholas R Burns, Ted Nettelbeck, Carlene Wilson and Gary Witter

A Scoping Review of Interactions between Omega-3 Long-Chain Polyunsaturated Fatty Acids and Genetic Variation in Relation to Cancer Risk

This scoping review examines the interaction of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and genetic variants of various types of cancers. A comprehensive search was performed to identify controlled and observational studies conducted through August 2017. Eighteen unique studies were included: breast cancer (n = 2), gastric cancer (n = 1), exocrine pancreatic cancer (n = 1), chronic lymphocytic leukemia (n = 1), prostate cancer (n = 7) and colorectal cancer (n = 6). An additional 13 studies that focused on fish intake or at-risk populations were summarized to increase readers&rsquo; understanding of the topic based on this review, DHA and EPA interact with certain genetic variants to decrease breast, colorectal and prostate cancer risk, although data was limited and identified polymorphisms were heterogeneous. The evidence to date demonstrates that omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) may decrease cancer risk by affecting genetic variants of inflammatory pathways, oxidative stress and tumor apoptosis. Collectively, data supports the notion that once a genetic variant is identified, the benefits of a targeted, personalized therapeutic regimen that includes DHA and/or EPA should be considered

Omega 3 fatty acid for the prevention of cognitive decline and dementia.

BACKGROUND: Evidence from observational studies suggests that diets high in omega-3 long-chain polyunsaturated fatty acids (PUFA) may protect people from cognitive decline and dementia. The strength of this potential protective effect has recently been tested in randomised controlled trials. OBJECTIVES: To assess the effects of omega-3 PUFA supplementation for the prevention of dementia and cognitive decline in cognitively healthy older people. SEARCH METHODS: We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 6 April 2012 using the terms: "omega 3", PUFA, "fatty acids", "fatty acid", fish, linseed, eicosapentaenoic, docosahexaenoic. SELECTION CRITERIA: Randomised controlled trials of an omega-3 PUFA intervention which was provided for a minimum of six months to participants aged 60 years and over who were free from dementia or cognitive impairment at the beginning of the study. Two review authors independently assessed all trials. DATA COLLECTION AND ANALYSIS: The review authors sought and extracted data on incident dementia, cognitive function, safety and adherence, either from published reports or by contacting the investigators for original data. Data were extracted by two review authors. We calculated mean difference (MD) or standardised mean differences (SMD) and 95% confidence intervals (CI) on an intention-to-treat basis, and summarised narratively information on safety and adherence. MAIN RESULTS: Information on cognitive function at the start of a study was available on 4080 participants randomised in three trials. Cognitive function data were available on 3536 participants at final follow-up.In two studies participants received gel capsules containing either omega-3 PUFA (the intervention) or olive or sunflower oil (placebo) for six or 24 months. In one study, participants received margarine spread for 40 months; the margarine for the intervention group contained omega-3 PUFA. Two studies had cognitive health as their primary outcome; one study of cardiovascular disease included cognitive health as an additional outcome.None of the studies examined the effect of omega-3 PUFA on incident dementia. In two studies involving 3221 participants there was no difference between the omega-3 and placebo group in mini-mental state examination score at final follow-up (following 24 or 40 months of intervention); MD -0.07 (95% CI -0.25 to 0.10). In two studies involving 1043 participants, other tests of cognitive function such as word learning, digit span and verbal fluency showed no beneficial effect of omega-3 PUFA supplementation. Participants in both the intervention and control groups experienced either small or no cognitive declines during the studies.The main reported side-effect of omega-3 PUFA supplementation was mild gastrointestinal problems. Overall, minor adverse events were reported by fewer than 15% of participants, and reports were balanced between intervention groups. Adherence to the intervention was on average over 90% among people who completed the trials. All three studies included in this review are of high methodological quality. AUTHORS' CONCLUSIONS: Direct evidence on the effect of omega-3 PUFA on incident dementia is lacking. The available trials showed no benefit of omega-3 PUFA supplementation on cognitive function in cognitively healthy older people. Omega-3 PUFA supplementation is generally well tolerated with the most commonly reported side-effect being mild gastrointestinal problems.Further studies of longer duration are required. Longer-term studies may identify greater change in cognitive function in study participants which may enhance the ability to detect the possible effects of omega-3 PUFA supplementation in preventing cognitive decline in older people