Edward B. Nelson

Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: A randomized trial

CONTEXT Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology. OBJECTIVE To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimers Disease Cooperative Study. INTERVENTION Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months. MAIN OUTCOME MEASURES Change in the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102). RESULTS A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51-9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72-9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44-3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44-3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm(3) (95% CI, 21.4-28.0 cm(3)) during 18 months and a 1.32% (95% CI, 1.14%-1.50%) volume decline per year compared with 24.0 cm(3) (95% CI, 20-28 cm(3)) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%-1.51%) volume decline per year (P = .79). CONCLUSION Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00440050.

Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline

Docosahexaenoic acid (DHA) plays an important role in neural function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly adults and in patients with Alzheimers disease. Higher DHA intake is inversely correlated with relative risk of Alzheimers disease. The potential benefits of DHA supplementation in age‐related cognitive decline (ARCD) have not been fully examined.

Effects of long-chain polyunsaturated fatty acid supplementation on neurodevelopment in childhood: a review of human studies.

Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LCPUFA) are critical for infant and childhood brain development, but levels of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are often low in the Western diet. Increasing evidence from both epidemiological and intervention studies, reviewed here, indicates that DHA supplementation, during pregnancy, lactation, or childhood plays an important role in childhood neurodevelopment. Arachidonic acid (ARA) is also important for infant growth and development. Several studies have demonstrated positive associations between blood DHA levels and improvements on tests of cognitive and visual function in healthy children. Controlled trials also have shown that supplementation with DHA and EPA may help in the management of childhood psychiatric disorders, and improve visual and motor functions in children with phenylketonuria. In all studies, DHA and EPA supplementation is typically well tolerated. Further research is needed to determine optimal doses for efficacy at different developmental ages. The potential long-term benefits of early LCPUFA supplementation also require consideration.

Clinical Overview of Algal-Docosahexaenoic Acid: Effects on Triglyceride Levels and Other Cardiovascular Risk Factors

The cardiovascular benefits of fish-derived long-chain polyunsaturated fatty acids, docosahexaenoic acid (DHA), and eicosapentaenoic acid are well established. Less studied are specific effects of individual long-chain polyunsaturated fatty acids. Based on data from 16 published clinical trials, this review examines effects of DHA triglyceride (TG) oil derived from algae (algal-DHA) on serum TG levels and related parameters. Study populations included subjects with both normal and elevated TG levels including those with persistent hypertriglyceridemia treated with concomitant 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. At doses of 1-2 g/d, algal-DHA significantly lowered plasma TG levels (up to 26%) either administered alone or in combination with statins. The reduction in TG levels was markedly greater in hypertriglyceridemic than in normal subjects. Algal-DHA modestly increased plasma levels of both high-density lipoprotein and low-density lipoprotein cholesterol. The increased plasma level of low-density lipoprotein cholesterol was associated with a shift of lipoprotein particle size toward larger, less atherogenic subfractions. In some subjects, blood pressure and heart rate were significantly reduced. Algal-DHA was safe and well tolerated. Unlike fish oil, algal-DHA seldom caused gastrointestinal complaints such as fishy taste and eructation, attributes of importance for patient compliance in high-dose therapy. Regression analysis that showed a linear relationship between baseline TG and magnitude of TG reduction suggests that a study of patients with very high TG levels (>500 mg/dL) is warranted. Future pharmacologic therapies for treating hypertriglyceridemia may include algal-DHA.

Efficacy of nonprescription doses of ibuprofen for treating migraine headache. a randomized controlled trial.

Objective.—To evaluate the efficacy and safety of ibuprofen, 200 mg and 400 mg, compared with placebo and each other for the treatment of pain of migraine headache.

The Relationship of Docosahexaenoic Acid (DHA) with Learning and Behavior in Healthy Children: A Review

Childhood is a period of brain growth and maturation. The long chain omega-3 fatty acid, docosahexaenoic acid (DHA), is a major lipid in the brain recognized as essential for normal brain function. In animals, low brain DHA results in impaired learning and behavior. In infants, DHA is important for optimal visual and cognitive development. The usual intake of DHA among toddlers and children is low and some studies show improvements in cognition and behavior as the result of supplementation with polyunsaturated fatty acids including DHA. The purpose of this review was to identify and evaluate current knowledge regarding the relationship of DHA with measures of learning and behavior in healthy school-age children. A systematic search of the literature identified 15 relevant publications for review. The search found studies which were diverse in purpose and design and without consistent conclusions regarding the treatment effect of DHA intake or biomarker status on specific cognitive tests. However, studies of brain activity reported benefits of DHA supplementation and over half of the studies reported a favorable role for DHA or long chain omega-3 fatty acids in at least one area of cognition or behavior. Studies also suggested an important role for DHA in school performance.

Safety evaluation of single cell oils and the regulatory requirements for use as food ingredients.

Publisher Summary Safety refers to a “reasonable certainty of no harm” based on an intellectual concept, not an inherent property of a substance. Tolerability refers to the capacity a subject has to consume a substance without the occurrence of an adverse event or the appearance of an increased sensitivity to the substance. Three processes are often used when considering the safety or tolerability of Single Cell Oils (SCOs). The first involves risk assessment, and the second and third processes involve risk management (regulation and control) and risk communication. This chapter discusses the general aspects of the safety and tolerability of SCOs. Safety evaluation of food ingredients, including SCOs, is based on a reasonable assumption that such ingredients do not cause any harm. The FDA Redbook was prepared to assist in the design of protocols for animal studies conducted to test the safety of food ingredients and includes detailed guidelines for testing the effects of food ingredients. The chapter also discusses the regulatory pathway for obtaining pre-market clearance of SCOs for use as food ingredients in the U.S. and as novel food ingredients in the EU, Australia, New Zealand, and Canada, citing some of the more recent published approvals for the oils.

Preclinical safety evaluation in rats using a highly purified ethyl ester of algal-docosahexaenoic acid

Preclinical studies have shown that docosahexaenoic acid (DHA) derived from microalgae (DHASCO) is neither mutagenic nor toxic in acute, subchronic or developmental tests. DHASCO, triglyceride oil from the fermentation of Crypthecodinium cohnii, contains 40-50% (400-500 mg/g) of DHA by weight. Martek Biosciences Corporation has developed a concentrated ethyl ester of DHA (900 mg/g) from DHASCO (MATK-90). A 90-day subchronic safety study with a one-month recovery period using Sprague-Dawley rats included clinical observations, ophthalmic examination, hematology, clinical chemistry, toxicokinetic evaluation, and pathological assessments. Effects of MATK-90 were compared with those produced from DHASCO and control (corn oil). Doses of MATK-90 (1.3, 2.5 and 5.0 g/kg/day) and DHASCO (5.0 g/kg/day=2g of DHA) were administered once-daily by oral gavage at a volume of 10 mL/kg. The corn oil was also administered by oral gavage (10 mL/kg/day). There were no treatment-related adverse effects in any of the parameters measured at doses of <or= 2.5 g/kg/day of MATK-90 or at 5.0 g/kg/day of DHASCO. In the mesenteric lymph node, marked macrophage infiltration was observed in 3 of 19 animals in the 5.0 g/kg/day MATK-90 treatment group and was considered to be adverse. The no-observable-adverse-effect level (NOAEL) for MATK-90 under the conditions of this study was 2.5 g/kg/day.

Role of Fatty Acids in the Neurological Development of Infants

The long-chain polyunsaturated fatty acids (LCPUFAs), docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6), are essential structural components of the central nervous system [1–4]. DHA is of particular importance because it is specifically concentrated in the structural membrane lipids of the white and gray matter of the brain and the visual elements of the retina [1, 4]. The human brain undergoes rapid growth during the first 2 years of life [5] during which there is a large concomitant accumulation of DHA [2]. Based on autopsy information, from the third trimester to about 2 years of age, there is a 12-fold increase in brain size. The increase in brain size is accompanied by an approximate fourfold increase in DHA and ARA concentrations in tissue [6].

Oral Nutrient Supplementation and Cognitive Function

The primary limitation of this study is that we were unable to determine the exact circumstances of office visits. Patients or referring clinicians may have requested office visits prior to the procedure, and we did not determine whether individual office visits were necessary or appropriate. The higher CCI among patients with office visits indicates some selection of patients at higher risk of adverse events for office visits, suggesting that our estimate is likely the upper limit of office visits that could be averted through increased direct access. We were unable to determine whether office visits prevented any unnecessary colonoscopies or improved the safety or clinical value of the colonoscopy. Our population included only younger individuals (<65 years) with private insurance, so our findings may not be generalizable to other populations. Although the precolonoscopy office visits added a modest