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A combined DHA-rich fish oil and cocoa flavanols intervention does not improve cognition or brain structure in older adults with memory complaints: results from the CANN randomized, controlled parallel-design study.
Vauzour, D, Scholey, A, White, DJ, Cohen, NJ, Cassidy, A, Gillings, R, Irvine, MA, Kay, CD, Kim, M, King, R, et al
The American journal of clinical nutrition. 2023;118(2):369-381
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At a population level, interventions that delay the onset of dementia by 2 years are predicted to reduce the number of dementia patients by 20%. Prospective cohort studies have consistently reported cognitive and neurophysiological benefits of the fish-derived omega-3 long-chain polyunsaturated fatty acids (PUFAs), EPA, and DHA and plant-derived flavanols (FLAVs). This study hypothesised that 12-month administration of a combination of 500 mg cocoa FLAVs with 1.5g omega-3 long-chain PUFAs would improve cognitive function in a mixed subjective cognitive impairment and mild cognitive impairment cohort. This study is based on the results of the CANN randomised controlled trial. A total of 258 participants were recruited and randomised to control or test intervention. Following baseline measurements, 125 participants were randomised into the active OM3FLAV intervention group and 121 into the control group. Results showed that the 1-year intervention with EPA and DHA and cocoa FLAVs did not improve cognition or protect the brain against atrophy in older adults with evidence of memory deficits. Authors concluded that given the complexity of neuropathological processes underpinning cognitive decline and dementia risk, multidomain, multinutrient, or whole diet approaches may be needed to positively impact the cognitive trajectory in the medium term (months to 3 years).
Abstract
BACKGROUND There is evidence that both omega-3 long-chain polyunsaturated fatty acids (PUFAs) (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and cocoa flavanols can improve cognitive performance in both healthy individuals and in those with memory complaints. However, their combined effect is unknown. OBJECTIVES To investigate the combined effect of EPA/DHA and cocoa flavanols (OM3FLAV) on cognitive performance and brain structures in older adults with memory complaints. METHODS A randomized placebo-controlled trial of DHA-rich fish oil (providing 1.1 g/d DHA and 0.4 g/d EPA) and a flavanol-rich dark chocolate (providing 500 mg/d flavan-3-ols) was conducted in 259 older adults with either subjective cognitive impairment or mild cognitive impairment. Participants underwent assessment at baseline, 3 mo, and 12 mo. The primary outcome was the number of false-positives on a picture recognition task from the Cognitive Drug Research computerized assessment battery. Secondary outcomes included other cognition and mood outcomes, plasma lipids, brain-derived neurotrophic factor (BDNF), and glucose levels. A subset of 110 participants underwent structural neuroimaging at baseline and at 12 mo. RESULTS 197 participants completed the study. The combined intervention had no significant effect on any cognitive outcomes, with the exception of reaction time variability (P = 0.007), alertness (P < 0.001), and executive function (P < 0.001), with a decline in function observed in the OM3FLAV group (118.6 [SD 25.3] at baseline versus 113.3 [SD 25.4] at 12 mo for executive function) relative to the control, and an associated decrease in cortical volume (P = 0.039). Compared with the control group, OM3FLAV increased plasma HDL, total cholesterol ratio (P < 0.001), and glucose (P = 0.008) and reduced TG concentrations (P < 0.001) by 3 mo, which were sustained to 12 mo, with no effect on BDNF. Changes in plasma EPA and DHA and urinary flavonoid metabolite concentrations confirmed compliance to the intervention. CONCLUSIONS These results suggest that cosupplementation with ω-3 PUFAs and cocoa flavanols for 12 mo does not improve cognitive outcomes in those with cognitive impairment. This trial was registered at clinicaltrials.gov as NCT02525198.
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Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease.
Patrick, RP
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019;33(2):1554-1564
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Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by progressive memory loss, spatial disorientation, cognitive impairment and behavioural changes. Ageing is the main risk factor for AD, with approximately one-third of Americans over the age of 85 being affected by the condition. The APOE gene provides instructions for making the apolipoprotein E family of proteins that are involved in fat metabolism and cholesterol transport. There are three different variants of this gene, one inherited from each parent. The variant called APOE4 is thought to increase AD risk from 2-3-fold (one inherited copy) to as much as 15-fold (two inherited copies), compared to individuals who do not carry this variant. The omega-3 oil docosahexaenoic acid (DHA) is an essential fatty acid, which comprises approximately 30% of the fats found in the human brain. Low levels of DHA in the brain increase the risk of developing AD, while normal and high levels may prevent the condition and ameliorate symptoms. This review paper brings together several lines of evidence on why individuals with the APOE4 gene variant don’t respond well to DHA supplementation but experience positive effects from dietary intake of DHA. The author suggests that this is due to the different forms of DHA found in dietary and supplemental sources. Some of the DHA present in fish and seafood is in phospholipid form, which is metabolised into lysophosphatidylcholine DHA (DHA-lysoPC) in the body. In contrast, fish oil supplements contain no DHA in phospholipid form, but in other forms that are mostly metabolised to free DHA. This paper puts forward an argument that, due to the breakdown of the integrity of the blood-brain barrier, APOE4 carriers have impaired brain transport of free DHA but not DHA-lysoPC. The author concludes that dietary sources that contain high amounts of DHA in phospholipid form, such as fish and fish roe may help increase plasma levels of DHA-lysoPC, which may be better transported to the brains of APOE4 carriers. She also highlights the pressing need for future clinical trials to evaluate the effects of omega-3 oils in phospholipid form on the cognitive function of APOE4 carriers with AD.
Abstract
Dietary and supplemental intake of the ω-3 fatty acid docosahexaenoic acid (DHA) reduces risk of Alzheimer's disease (AD) and ameliorates symptoms. The apolipoprotein E ( APOE) 4 allele is the strongest risk factor for sporadic AD, exclusive of age. APOE4 carriers respond well to the DHA present in fish but do not respond as well to dietary supplements. The mechanisms behind this varied response remain unknown. I posit that the difference is that fish contain DHA in phospholipid form, whereas fish oil supplements do not. This influences whether DHA is metabolized to nonesterified DHA (free DHA) or a phospholipid form called lysophosphatidylcholine DHA (DHA-lysoPC). Free DHA is transported across the outer membrane leaflet of the blood-brain barrier (BBB) via passive diffusion, and DHA-lysoPC is transported across the inner membrane leaflet of the BBB via the major facilitator superfamily domain-containing protein 2A. I propose that APOE4 carriers have impaired brain transport of free DHA but not of DHA-lysoPC, as a consequence of a breakdown in the outer membrane leaflet of the BBB, putting them at increased risk for AD. Dietary sources of DHA in phospholipid form may provide a means to increase plasma levels of DHA-lysoPC, thereby decreasing the risk of AD.-Patrick, R. P. Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease.
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Food for Mood: Relevance of Nutritional Omega-3 Fatty Acids for Depression and Anxiety.
Larrieu, T, Layé, S
Frontiers in physiology. 2018;9:1047
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The human brain contains high levels of polyunsaturated fatty acids (PUFAs). Of these PUFAs, omega-3s have been widely studied in relation to many brain diseases, including anxiety and depression. This review focuses on the clinical and experimental data linking dietary intake of omega-3s with depression or anxiety. People diagnosed with anxiety and depressive disorders have lower omega-3s and a higher ratio of omega-6s to omega-3s in their blood and brains compared to healthy subjects. Experiments on omega-3 supplementation for depression and post-traumatic stress have had promising results. Numerous mechanisms have been proposed for the effects of omega-3s. These include direct effects on specific receptors in the brain, regulation of the endocannabinoid system, effects on the hypothalamic-pituitary-adrenal (HPA) axis, and reduction of inflammation in the brain. The authors conclude that more research is needed into the potential of omega-3s as treatment for mood-related diseases.
Abstract
The central nervous system (CNS) has the highest concentration of lipids in the organism after adipose tissue. Among these lipids, the brain is particularly enriched with polyunsaturated fatty acids (PUFAs) represented by the omega-6 (ω6) and omega-3 (ω3) series. These PUFAs include arachidonic acid (AA) and docosahexaenoic acid (DHA), respectively. PUFAs have received substantial attention as being relevant to many brain diseases, including anxiety and depression. This review addresses an important question in the area of nutritional neuroscience regarding the importance of ω3 PUFAs in the prevention and/or treatment of neuropsychiatric diseases, mainly depression and anxiety. In particular, it focuses on clinical and experimental data linking dietary intake of ω3 PUFAs and depression or anxiety. In particular, we will discuss recent experimental data highlighting how ω3 PUFAs can modulate neurobiological processes involved in the pathophysiology of anxiety and depression. Potential mechanisms involved in the neuroprotective and corrective activity of ω3 PUFAs in the brain are discussed, in particular the sensing activity of free fatty acid receptors and the activity of the PUFAs-derived endocannabinoid system and the hypothalamic-pituitary-adrenal axis.