Cognition and Omega-3 fatty acids.

Thoughts, feelings, perceptions and actions are all products of the workings of the human brain. These activities depend on the architecture of the brain and the way it works. To understand the structure of the brain, we must consider its components and the extensive network of linkages between them. These paths and circuits form the anatomical basis for information processing (Figure 1).

All human beings have about 100 to 150 billion neurons; the assembly of these building blocks into circuits is what underlies both the simplest and the most complex of our abilities and talents. Each neuron receives inputs from many parts of the nervous system and distributes information to other nerve cells. The neurons collect signals from several sources, analyse and integrate the information, transform it, convert it into complex output signals and disseminate these signals to many other strands of the neural pathway. These signals are mediated by two completely different mechanisms that work in sequence: the conduction of electrical potentials and the release of chemical compounds, the so-called neurotransmitters that interact with the next cell in the nervous system. Neurons commonly found in the human brain have a dense population of dendrites that receive impulses from nerve cells located nearby.

Structurally, dendrites are the branched projections of a neuron that act to conduct the electrical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project. The neuron cell body contains the nucleus, which is responsible for the transcription of proteins that are vital for neuronal function, and extends into a single axon that ends in a network containing the axon terminals or synapses (Figure 2). The proteins produced in the nucleus are transported via microtubules and neurofilaments to the synapses that contain mitochondria, which are responsible for energy production, and the synaptic vesicles that store the different neurotransmitters (Figure 3).

As with elsewhere in the human body, the neuronal cell wall is composed of phospholipid molecules that form flexible bilayers (Figure 4). The phospholipid molecules are complex lipids that contain saturated, mono-unsaturated and polyunsaturated fatty acids (FAs). Dense segments--called lipid rafts--containing other lipids such as sphingolipids and cholesterol, interrupt these uniform layers; these enriched microdomains are densely populated with receptors and ion channels, both of which are important to the cell signalling system. The fatty acids in the phospholipid bilayers of brain neurons are different from other cells in the body, mainly because of the high concentration of docosahexaenoic acid (DHA) and arachidonic acid (ARA). These omega-3 (DHA) and omega-6 (ARA) type FAs have the highest number of double bonds in their hydrocarbon chain. Thus, when integrated into the phospholipid molecule, they occupy more space--because of the complex three-dimensional structure determined by the frequent double bonds (Figure 5).

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This typical brain lipid architecture, with its bulky fatty acids, provides the phospholipid membranes with a high degree of elasticity. The reason for this is not well understood, but it is generally agreed that a high concentration of DHA and ARA is closely linked to the basic functions of the neurons, such as the speed of electrical impulse propagation and the release and uptake of neurotransmitters. In addition to being structural elements of the neuronal cell wall, DHA and ARA are substrates for enzymes with a housekeeping function in the brain. DHA released from neuronal phospholipids by specific phospholipases binds to the enzyme, 15-lipoxygenase, forming docosanoids, some of which are known as neuroprotectins. These neuroprotectors exert actions that protect the neurons against oxidative and degenerative damage.

The brain is extremely susceptible to damage caused by head injuries, the deposition of pathologic compounds--such as amyloid, which causes Alzheimer's and dementia--lipid solvents such as alcohol, and hypoxia caused by vascular diseases. In fact, the brain shows a gradual loss of weight after the age of 30, and some parts of the brain may lose a larger proportion, such as the hippocampus region, which is particularly susceptible to degradation. These parts of the frontal brain lobes are closely related to cognitive functions, and computer tomography images of the brain in Alzheimer's patients regularly shows atrophy of this part of the brain. DHA has a protective effect on the hippocampal neurons and improves synaptic functions in the same type of neurons. (1,2) Alzheimer's patients, clinically characterized by progressive cognition defects, have low levels of DHA in the brain compared with age-matched controls, and they also demonstrate low concentrations of neuroprotectins in the hippocampal region. (3,4) Animal studies of transgenic models of Alzheimer's disease with amyloid deposition on neurons have demonstrated that DHA has preventive effects. (5)

Of Memory and Younger Days

Memory is related to a set of mental abilities that depend on several systems in the brain. (6) It is tempting to speculate that a regular intake of PUFAs--in particular the marine fatty acid, DHA--which has so many important functions in neurons, could improve such a complex function of the brain in healthy individuals and, even more importantly, that a regular intake of DHA could prevent the development of age-related cognition defects and Alzheimer's disease. In general, DHA, an essential fatty acid, is poorly converted from shorter-chain omega-3 fatty acids, and it therefore has to be provided by eating seafood or taking omega-3 supplements. By contrast, ARA is readily obtained from our diet. It has already been established that the integration of these polyunsaturated fatty acids (PUFAs) in the brains of unborn and newborn children is an important driver of visual acuity, intellectual functions and other brain functions. (7) And, in youngsters, high levels of marine omega-3 fatty acids have been positively associated with cognition. (8) In the Maastricht Aging Study, in which 241 participants of different ages were followed for 12 years, a high level of fish consumption was associated with better performance on memory tasks--even though the calculated DHA intake did not correlate with improved cognitive effects. (9) Children and adolescents demonstrate adequate DHA uptake when it is given either as seafood or, indeed, in the form of a DHA concentrate. The DHA plasma content also increases among elderly people in a similar way to young adults. (10) The question remains, however, whether eating fish or DHA concentrates makes you smarter. A European expert panel of paediatricians and nutritionists has recommended that pregnant and lactating women should have a daily intake of at least 200 mg of DHA to give their babies a good start in life. (11)

DHA for Old Age?

And what about the ageing population? Can they benefit from a regular intake of DHA? Conquer and collaborators were able to demonstrate that low DHA blood concentrations correlated with cognitive impairment in the elderly ... and even more so in Alzheimer's patients. (12) As previously mentioned, Alzheimer's disease is caused by the deposition of a pathological protein called amyloid, which starts an inflammatory process that leads to neuron cell death. In neuron cell cultures and animal studies, it has been demonstrated that amyloid formation can be prevented by the addition of DHA. (1,13) Cohort studies from the Netherlands, France and the USA have demonstrated that the regular intake of fish has a protective effect by preventing the development of Alzheimer's disease. (14-16) Recently, the results of the OmegAD study on early-stage Alzheimer's disease at the Karolinska Hospital in Sweden were published, demonstrating that a regular daily intake of 1.7 g of DHA (derived from the high-DHA concentrate, EPAX 1050TG) for 6 months could slow down cognitive decline in these patients. (17) Concomitantly, neuropsychiatric symptoms such as agitation and depression were favourably affected, demonstrating the complex interactions between memory and mental abilities. (18) Ongoing studies in Europe and the USA on this subset of patients will hopefully produce similar results, making it easier to draw firm conclusions about the effects of regular DHA supplementation. As eating fish is not the same as taking DHA supplements, it will also be important to distinguish between the effects of DHA alone and phospholipids containing DHA, which are the actual building blocks in the neurons.

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While we are waiting for these results, pregnant women should be encouraged to eat more fish or take DHA supplements during the last 3 months of pregnancy and while they are breastfeeding to ensure the optimal intellectual development of their child. Mothers who choose not to provide their babies with nature's first choice should buy infant formulas fortified with marine omega-3 FAs. And the rest of the population, who are expected to become very old and no doubt hope to retain good mental health throughout life, should eat more seafood or start taking a daily capsule or two of an omega-3 DHA concentrate.

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References

(1.) E. Calderon and H.Y. Kim, "Docosahexaenoic Acid Prevents Hippocampal Neuronal Apoptosis," ISSFAL 2008: p 63 (abstract).

(2.) D. Cao, et al., "DHA Enhances Synaptic Function in Hippocampal Neurons," J. Nutr. Biochem. 16, 538-546 (2005).

(3.) M. Soderberg, et al., "Fatty Acid Composition of Brain Phospholipids in Aging and Alzheimer's Disease," Lipids 26, 421-425 (1991).

(4.) N.G. Bazan, "New Understanding of Neurodegenerative Diseases and the Bioactivity of Omega-3 Fatty Acids," ISSFAL 2008: p 98 (abstract).

(5.) F. Calon, et al., "Docosahexaenoic Acid Protects from Dendritic Pathology in an Alzheimer's Disease Mouse Model," Neuron 43, 633-645 (2004).

(6.) A.E. Budson and B.H. Price, "Memory Dysfunction," N. Engl. J. Med. 352, 692-699 (2005).

(7.) J.R. Drover, et al., "Three Randomized Clinical Trials of Early Long-Chain PUFA Supplementation on Means-End Problem Solving in Nine Month-Olds," ISSFAL 2008: p 112 (abstract).

(8.) A. Sumich, et al., "Association Between Blood Levels of Omega-3 Fatty Acids and Cognition in Adolescents with ADHD: Verbal Intelligence and Memory," ISSFAL 2008: p149 (abstract).

(9.) R.H.M. De Groot, et al., "Plasma Phospholipid Fatty Acid Status and Cognitive Performance in Normal Healthy Aging Adults: Results from the 12 Year Follow-Up of the Maastricht Aging Study," ISSFAL 2008: p 212 (abstract).

(10.) M. Vandal, et al., "DHA Metabolism in the Healthy Elderly," ISSFAL 2007: p 214 (abstract).

(11.) B. Koletzko, et al., "Dietary Fat Intake for Pregnant and Lactating Women," Br. J. Nutr. 98(5), 873-877 (2007).

(12.) J.A. Conquer, et al., "Fatty Acid Analysis of Blood Plasma of Patients with Alzheimer's Disease, Other Types of Dementia and Cognitive Impairment," Lipids 35, 1305-1312 (2000).

(13.) G.P. Lim, et al., "A Diet Rich with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model," J. Neurosci. 25, 3032-3040 (2005).

(14.) S. Kalmijn, et al., "Dietary Fat Intake and the Risk of Incident Dementia in the Rotterdam Study," Ann. Neurol. 42, 776-782 (1997).

(15.) P. Barberger-Gateau, et al., "Fish, Meat and Risk of Dementia: Cohort Study," BMJ 325, 932-393 (2002).

(16.) M.C. Morris, et al., "Consumption of Fish and n-3 Fatty Acids and Risk of Incident Alzheimer's Disease," Arch. Neurol. 60, 940-946 (2003).

(17.) Y. Freund-Levi, et al., "Omega-3 Fatty Acid Treatment in 174 Patients with Mild-Moderate Alzheimer's Disease: The OmegAD Study," Arch. Neurol. 63,1402-1408 (2006).

(18.) Y. Freund-Levi, et al., "Omega-3 Supplementation in Mild to Moderate Alzheimer's Disease: Effects on Neuropsychiatric Symptoms," Int. J. Geriatr. Psychiatry 23(2), 161-169 (2008).

Morten Bryhn, MD, PhD Silentia AS, Norway

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