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Polyunsaturated Fats and Neurological Disorders

by C. Leigh Broadhurst, Ph.D.

from Nutrition Science News, Sept. 2000, Vol.5, No.9

For the past 50 years, major psychiatric disorders generally have been attributed to neurotransmitter system abnormalities. Neurotransmitters are biochemicals that transfer information from one neuron, or central nervous system cell, to another. While this concept is still considered valid, it has limited ability to explain the origins and guide the treatment of mental illness. Furthermore, there is a growing consensus in scientific circles that the phospholipid metabolism of the neuron cells themselves also plays a crucial role in the development of mental conditions.1 Phospholipids are substances composed of two fatty acids linked to a phosphate group (e.g. choline, serine, inositol). This consensus has come because numerous studies have linked low brain levels of these substances to conditions such as depression, dyslexia, schizophrenia and more.

Unlike other body membranes, neurons contain a very high percentage of long-chain polyunsaturated fatty acids (LC-PUFAs) because thay are used to construct complex structures such as the brain, which has very high rates of signal transfer and data processing. Excluding water, the mammalian brain is about 60 percent lipid (lipid is a general term for fatty biochemicals including phospholipids, triglycerides, ceramides and free fatty acids).

Polyunsaturated fatty acids (PUFAs) are sometimes called essential fatty acids because they cannot be synthesized by the body and therefore must be provided by the diet. There are only two precursor dietary essential PUFAs: alpha-linolenic acid (LNA, n-3) and linoleic acid (LA, n-6). In theory, these 18-carbon PUFAs can be converted to form predominately 20- and 22-carbon LC-PUFAs with four or more double bonds. However, the central nervous system is unique compared to other tissues because it connot directly use alpha-linolenic or linoleic acids, only their LC-PUFA derivates,2 which are mainly docosahexaenoic acid (DHA) and arachidonic acid (AA).

LC-PUFAs are the building material of the central nervous system and also are required for the normal behavior of cell signaling systems, which determine how neurons function. In the human brain, millions of neuronal microconnections are made between dendrites, the long, rootlike extensions of neurons. This signaling involves the release of chemical messengers from the phospholipids rich in DHA and AA that make up the denditic membrane (outer covering). These messengers - substances such as protaglandins and leukotrienes - allow for 'cross talk' between adjacent neurons.3

Why Brains become Deficient in LC-PUFAs

A substantial body of evidence links LC-PUFA deficiency to attention-deficit and/or hyperactivity disorders, dyslexia, senile dementia, clinical depression, bipolar disorder, schizophrenia, and other problems of a dual psychological and physiological nature.1 In research animals, many of these problems have been shown to operate in a multigenerational manner, increasing in severity as successive generations continue to be deficient in LC-PUFAs.4 There are two major reasons for these deficiencies.

  1. A scientific consensus is emerging that a systematic reduction in fish, shellfish, organ meats and wild game in our diets is causing widespread LC-PUFA deficiency. Put simply, our bodies are designed to function using a whole-foods, preagricultural diet much higher in LC-PUFAs. Foods richest in DHA and its precursor, eicosapentaenoic acid (EPA), are marine fish and shellfish from cold waters. Fish and shellfish from warmer marine or fresh water have ubiquitous DHA and EPA; however, the AA content is generally higher. Foods richest in AA are egg yolk, organ meats and muscle meats from land animals as well as tropical fish and shellfish.
  2. Although 90 percent of the PUFAs in the brain are DHA and AA, humans (and other mammals) are actually inefficient at producing these from their 18-carbon precursors, LA and LNA.5 Animal studies suggest why this may be so.
    • In the developing rat brain, direct incorporation of AA and DHA into neural tissue is 10 times greater than is acheived by synthesis from LA and LNA.6
    • In rat brains, 30 times as many molecules of brain DHA came from preformed DHA as compared to synthesis from LNA.6
    • More than 30 molecules of LNA within the rat brain are used to make brain cholesterol and the saturated-fat palmitic acid for every one molecule used to make DHA.7
    • Newborn baboons fed only LNA in formula were able to convert just 0.23 percent of ingested LNA to brain DHA. A conversion like this would supply only 9 percent of a human infant's DHA requirements. Note: These animal studies are invasive and cannot be done on humans.8
    • Contrary to popular opinion, synthesis of AA from LA is not efficient either. Only a small percentage of LA intake is actually converted to AA in rats and even less in humans. Vegans generally have stongly reduced blood levels of both AA and DHA.9
The recognition of such LC-PUFA deficiencies has led many researchers to investigate its connection to numerous psychiatric disorders. So far the correlations have been remarkably positive.

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Depression

In the past 100 years, the lifetime risk of developing major clinical depression has increased one hundredfold in North America. This increase coincides with the adoption of a diet based heavily on refined, processed agricultural commodities and a resultant dramatic reduction in n-3 PUFA consumption.10 Moreover, across 19 countries, the incidence of both major and postpartum depression increased as fish intake decreased.11 Studies have found that major depression is associated with low blood levels of DHA. Lack of DHA is not the sole cause of depression, but it is likely that individuals who may be genetically or situationally (i.e., experiencing trauma or chronic stress) susceptible to depression do poorly if DHA is deficient in their diets. Not only is low dietary DHA a problem, but prolonged psycholgical stress may actually deplete LC-PUFAa from neural membranes. In a 1995 multicenter European study conducted by a team at the Fidia Research Laboratories in Abano Terme, Italy, 494 elderly persons treated for six months with 90 mg per day DHA (contained in 300 mg bovine phosphatidyl serine) showed marked improvement in apathy and social withdrawal symptoms.12

Interestingly, a greater risk of coronary artery disease is also associated with low DHA levels. An overview of 83 studies found that coronary artery disease correlated more strongly with depression than any other personality trait.13 There is clear evidence that major depression occurring near the time of a heart attack increases the risk of a second (often deadly) heart attack in the first 24 hours and at 6, 12, and 18 months after the initial attack.13 Researchers are accepting that depression associated with cardiovascular disease has part of its origin in nutrient deficiencies, including DHA and B vitamins.

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Hyperactivity Disorders and Dyslexia

A good case can be made supporting the idea that hyperactivity disorders in children are a manifestation of a genetic requirement for dietary LC-PUFAs and gamma-linolenic acid (GLA). Conversion of LA and ALA to LC-PUFA and/or PUFA metabolites in hyperactive children is probably not adequate to maintain normal brain function, or the inadequate conversion exacerbates a preexisting brain abnormality. The deficiency is unlikely to be due to a lack of dietary PUFA, because typically only one member of a household/family is affected. The most likely cause is a specific biochemical bottleneck that prevents enough conversion of LA and ALA to metabolites such as eicosanoid hormones.

PUFA deficiency also has been linked to attention deficit-hyperactivity disorder (ADHD). A Purdue University study compared 53 boys with ADHD to 43 control non-ADHD boys. A subset of 21 ADHD boys had a 20 percent reduction of PUFA in blood plasma (both plasma and red cells were investigated) compared to the remaining 60 percent and to the controls.14 The subset was characterized by essential fatty acid deficiency symptoms such as eczema, dermatitis, excessinve thirst, frequent urination and brittle nails. All the ADHD boys also had higher incidences of allergies, asthma, colds, ear infections and stomachaches than controls. Thus, the ADHD boys showed evidence of the negative feedback cycle between inadequate nutrition, chronic allergies and hyperactive behavior.

In a second study by the same group at Purdue University, 96 boys ages 6-12 were found to have behavior, learning and health problems associated with low total PUFA levels, especially DHA.15 Essential fatty acid deficiency symptoms including thirst, frequent urination and dry skin were common in the boys, and those who were the most PUFA-deficient had more severe learning and behavior problems. Results of the first clinical trial in which children with ADHD were supplemented with DHA from marine algae are still being analyzed, but so far they are not promising. Apparently the behavior of both the control and ADHD children improved during the study, but there was no significant difference between the groups.16 It may be that only children who are PUFA deficient benefit markedly from short-term supplementation, or that the multifactorial nature of the disease precludes treatment with a single supplement.

Dyslexia is often characterized by a visual defect that decreases the eye's ability to adapt to the dark. In a 1995 controlled study conducted in Scotland, supplemental DHA at 480 mg per day for a month was shown to improve this problem in 10 dyslexics.17 Control subjects did not improve, except for one who was a vegan and consumed no DHA in his diet prior to this study. Reading ability and behavior were also reported to improve with DHA supplementation.

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Senile Dementia and Alzheimer's Disease

In research animals, the ability to convert ALA to DHA and LA to GLA lessons with age. Thus it's been proposed that the resulting deficiency in GLA, AA and DHA could be a key factor in aging. A 1997 University of Dundee study of body fat samples from more than 10,000 Scottish individuals aged 40 to 59 found that the GLA/LA ratio decreased with age, independent of diet.18 Fatty acid determinations in elderly humans confirm LA metabolites decline with age.

Reduced levels of PUFAs have been observed in blood samples from Alzheimer's patients and those suffering from other forms of dementia. DHA is apparently selectively incorporated into brain synapses, and depletion is known to result in reduced cognitive ability. Higher levels of fish consumption were correlated to a lower incidence of dementia, including Alzheimer's dementia, in a study of 5,386 Dutch persons over age 55.19 In a 1999 study, 20 elderly Japanese (average age 83) with stroke-related dementia received 720 mg DHA or placebo for one year. Those receiving DHA had improvements in cognition and memory compared to controls.20

Excessive oxidation of PUFAs in neuronal cell membranes may play a role in the development of Alzheimer's and related dementias. Studies have shown that higher blood levels of vitamin or phytochemical antioxidants are associated with better cognition in older persons. For example, a 4.3-year follow-up of 633 Americans over age 65, conducted at Rush University in Chicago, found that 91 developed Alzheimer's disease.20 None of the 50 persons who supplemented vitamin C and/or E were among the 91 who developed the disease. Prevention and treatment of dementias may be enhanced by the simultaneous supplementation of antioxidants, fish oil and evening primrose or borage oil.

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Schizophrenia and Bipolar Disorder

Schizophrenia is the most extensively studied neurological disease in relation to lipid metabolism. Red blood cell fatty acids measured in schizophrenics from Ireland, England, Scotland, Japan and the United States have been shown to contain lower than normal levels of AA and DHA, and of PUFAs in general. Schizophrenia may manifest itself when at least two genetic abnormalities in fatty acid metabolism are simultaneously present: an increased rate of removal of PUFAs, especially AA and DHA from phospholipid cell membranes; and a reduced rate of incorporation of these same PUFAs in the cell membranes.22

Supplementation of particular LC-PUFAs does not "turn off" the aberrant genes, but may partially compensate for their abnormal functioning. Since 1981, eight studies have supplemented schizophrenic patients (remaining on antipsychotic medications) with various PUFAs. The greatest improvement in symptoms was seen with an EPA-enriched fish oil.23 The rationale for LC-PUFA supplementation for schizophrenics is supported by a 1988 World Health Organization (WHO) survey of the incidence and outcome of schizophrenia in eight countries in Africa, Asia, Europe and the Americas. WHO found that the incidence of schizophrenia was similar in all locations, but the outcomes were very different.24 More intractable, severe cases were associated with higher levels of saturated fat in the diet, but less severe cases were associated with diets rich in vegetables and fish.

Schizophrenia does not "come out of the blue." Individuals who grow up to develop schizophrenia as teens or adults often suffered from defects in verbal and social skills, including dyslexia, low IQ, attention-deficits and an inability to form friendships during childhood. In addition, adult relatives of schizophrenics who are not schizophrenic have an increased incidence of these defects. Bipolar disorder, alcoholism and schizotypy (antisocial, "disconnected" personality disorder) are also more common in relatives of schizophrenics.

David Horrobin, Ph.D., of Laxdale Research in Stirling, Scotland, has proposed an explanation for these familial trends in mental illness: Dyslexia and schizotypy arise when only the defect in PUFA incorporation is present.24 Therapeutic doses of lithium inhibit this increased PUFA removal, shedding new light on why this drug has been a successful treatment for bipolar disorder. A 1998 trial at Brigham and Women's Hospital in Boston gave 30 bipolar patients 9.6 grams per day of DHA plus EPA or olive oil placebo for four months.25 LC-PUFA treatment improved symptoms and increased the period of remission of depression compared to placebo.

LC-PUFA deficiency explains why mental illness arises from both genetic and environmental influences. Overall, humans aren't very good at converting PUFAs to LC-PUFAs, and some individuals may have genetic or health conditions that virtually preclude conversion. Others may have genetic conditions that don't allow LC-PUFAs to remain in neuronal membranes where it belongs. however, we can alter these situations for the better by choosing a diet rich in LC-PUFAs or by taking appropriate supplements. These days a variety of PUFA supplements are already being offered, and they should be considered essential nutrients that can help treat and prevent mental illness in a suprisingly safe, simple and noncontroversial manner.

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C. Leigh Broadhurst, Ph.D., heads 22nd Century Nutrition, a nutrition/scientific consulting firm, and is the author of Diabetes: Prevention and Cure (Kensington Publishing, 1999).

References

  1. Peet MI, et al. editors. Phospholipid spectrum disorder in psychiatry. Carnforth, UK: Marius Press; 1999.
  2. Broadhurst CL, et al. Rift Valley lake fish and shellfish provided brain specific nutrition for early Homo. Br J Nutr 1998;79:3-21.
  3. Clandinin MT. Brain development and assessing the supply of polyunsaturated fatty acid. Lipids 1999;34:131-7.
  4. Jensen MM, et al. Correlation between level of (n-3) polyunsaturated fatty acids in brain phospholipids and learning ability in rats. A multiple generation study. Biochim Biophys Acta 1996;1300:203-9.
  5. Gerster H. Can adults adequately convert a-linolenic acid (18:3n-3) to eicosapentaneoic acid (20:5n-3) and docosahexanoic acid (22:6n-3)? Internat J Vit Nutr Res 1998;68:159-73.
  6. Crawford MA, et al. Evidence for the unique function of docosahexaenoic acid during the evolution of the modern hominid brain. Lipids 1999;34:S39-S47.
  7. Cunnane SC, et al. Utilization of uniformly labelled 13C polyunsaturated fatty acids in the synthesis of long chain fatty acids and cholesterol accumulating in the neonatal rat brain. J Neurochem 1994;62:2429-36.
  8. Su HM, et al. Bioequivalence of dietary a-linolenic acid and docosahexaenoic acids as sources of docosahexanoate accretion in brain and associated organs of neonatal baboons. Pediatr Res 1999;45:1-7.
  9. Pauletto P, et al. Blood pressure and atherogenic lipoprotein profiles of fish-diet and vegetarian villagers in Tanzania: the Lugalawa study. Lancet 1996;348:784-8.
  10. Hibbeln JR. Salem N. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr 1995;62:1-9.
  11. Hibbeln JR. Long-chain polyunsaturated fatty acids in depression and related conditions. In Peet, MI, et al., editors. Phospholipid spectrum disorder in psychiatry: Carnforth, UK: Marius Press; 1999.p 195-210.
  12. Cenacchi, T, et al. Cognitive decline in the elderly. A double-blind placebo-controlled multicenter study on efficacy of phosphatidyl serine administration. Aging Clin Exp Res 1993;5:123-33.
  13. Booth-Kewley S, Friedman HS. Psychological predictors of heart disease: a quantitative review. Psychol Bull 1987;101:343-62.
  14. Stevens LJ, et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 1995;62:761-8.
  15. Stevens LJ, et al. Omega-3 fatty acids in boys with behavior, learning, and health problems. Physiol Behav 1996;59:915-20.
  16. Personal Communication, David Kyle, Research Director, Martek Biosciences Inc. at 4th Congress of the International Society for the Study of Fats and Lipids, Tsukuba, Japan, June 4-9, 2000.
  17. Stordy, BJ Dyslexia, attention deficit hyperactivity disorder, dyspraxia -- do fatty acids help? Dyslexia Rev 1997;9:1-3.
  18. Bolton-Smith C, et al. Evidence for age-related differences in the fatty acid composition of human adipose tissue, independent of diet. Eur J Clin Nutr 1997;51:619-24.
  19. Kalmijn S, et al. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 1997;42:776-82.
  20. Terano T, et al. Docosahexanoic acid supplementation improves the moderately severe dementia from thrombotic cerebrovascular diseases. Lipids 1999;34:S345-46.
  21. Morris MC, et al. Vitamin E and vitamin C supplement use and risk of incedent Alzheimer's disease. Alzheimer Dis Assoc Disord 1998;12:121-26.
  22. Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenis. Schizophr Res 1998;30:193-208.
  23. Peet M, et al. Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenia patients, and the clinical effects of dietary supplementation. Prost Leukot Essent Fatty Acids 1996;55:71-5.
  24. Christensen O and Christensen E. Fat consumption and schizophrenia. Acta Psychiatr Scand 1988;78:586-91.
  25. Stoll AL, et al. Omega 3 fatty acids in bipolar disorder. Arch Gen Psychiatry 1999;56:407-12.

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