Chapter  114:  Effects of Omega-3 Fatty Acids on Cognitive Function with Aging, Dementia, and Neurological Diseases

The Recognition of Essential Fatty Acids

Dietary fat has long been recognized as an important source of energy for mammals, but in the late 1920s, researchers demonstrated the dietary requirement for particular fatty acids, which came to be called essential fatty acids. It was not until the advent of intravenous feeding, however, that the importance of essential fatty acids was widely accepted: Clinical signs of essential fatty acid deficiency are generally observed only in patients on total parenteral nutrition who received mixtures devoid of essential fatty acids or in those with malabsorption syndromes. These signs include dermatitis and changes in visual and neural function. Over the past 40 years, an increasing number of physiological functions, such as immunomodulation, have been attributed to the essential fatty acids and their metabolites, and this area of research remains quite active.^{1, 2}

Fatty Acid Nomenclature

The fat found in foods consists largely of a heterogeneous mixture of triacylglycerols (triglycerides)--glycerol molecules that are each combined with three fatty acids. The fatty acids can be divided into two categories, based on chemical properties: saturated fatty acids, which are usually solid at room temperature, and unsaturated fatty acids, which are liquid at room temperature. The term “saturation” refers to a chemical structure in which each carbon atom in the fatty acyl chain is bound to (saturated with) four other atoms, these carbons are linked by single bonds, and no other atoms or molecules can attach; unsaturated fatty acids contain at least one pair of carbon atoms linked by a double bond, which allows the attachment of additional atoms to those carbons (resulting in saturation). Despite their differences in structure, all fats contain approximately the same amount of energy (37 kilojoules/gram, or 9 kilocalories/gram).

The class of unsaturated fatty acids can be further divided into monounsaturated and polyunsaturated fatty acids. Monounsaturated fatty acids (the primary constituents of olive and canola oils) contain only one double bond. Polyunsaturated fatty acids (PUFAs) (the primary constituents of corn, sunflower, flax seed, and many other vegetable oils) contain more than one double bond. Fatty acids are often referred to using the number of carbon atoms in the acyl chain, followed by a colon, followed by the number of double bonds in the chain (e.g., 18:1 refers to the 18-carbon monounsaturated fatty acid, oleic acid; 18:3 refers to any 18-carbon PUFA with three double bonds).

Table 1.1 Nomenclature of omega-3 fatty acids

Table 1.1 Nomenclature of omega-3 fatty acids

Names		Abbreviations
Trivial	IUPAC*	Carboxyl-reference	Omega-reference	Other
Linolenic acid	9, 12, 15-octadecenoic acid	18:3Δ9 12 15	18:3n-3	ALA
	alpha-linolenic acid		18:3 (ω-3)	α-LA
				LNA
				α-LNA
Docosahexaenoic acid	4, 8, 12, 15, 19- docosahexaenoic acid	22:6Δ4 8 12 15 19	22:6n-3	DHA
	cervonic acid		22:6 (ω-3)
Docosapentaenoic acid	7, 10, 13, 16, 19- docosapentaenoic acid	22:5Δ7 10 13 16 19	22:5n-3	DPA
			22:5 (ω-3)
Eicosapentaenoic acid	5, 8, 11, 14, 17- eicosapentaenoic acid	20:5Δ5 8 11 14 17	20:5n-3	EPA
Icosapentaenoic acid			20:5 (ω-3)
Timnodonic acid

*

IUPAC=International Union of Pure and Applied Chemistry

Finally, PUFAs can be categorized according to their chain length. The 18-carbon n-3 and n-6 shorter-chain PUFAs are precursors to the longer 20- and 22-carbon PUFAs, called very-long-chain PUFAs (VLCPUFAs).

Fatty Acid Metabolism

Mammalian cells can introduce double bonds into all positions on the fatty acid chain except the n-3 and n-6 position. Thus, the shorter-chain alpha-linolenic acid (ALA, chemical abbreviation: 18:3n-3) and linoleic acid (LA, chemical abbreviation: 18:2n-6) are essential fatty acids. No other fatty acids found in food are considered ‘essential’ for humans, because they can all be synthesized from the shorter chain fatty acids.

Figure 1. Classical Omega-3 and Omega-6 Fatty acid (more...)

   Figure 1. Classical Omega-3 and Omega-6 Fatty acid synthesis pathways and the role of omega-3 fatty acid in regulating health/disease markers

Figure 1.1

The omega-6 fatty acid LA is converted to gamma-linolenic acid (GLA, 18:3n-6), an omega-6 fatty acid that is a positional isomer of ALA. GLA, in turn, can be converted to the longer-chain omega-6 fatty acid, arachidonic acid (AA, 20:4n-6). AA is the precursor for certain classes of an important family of hormone-like substances called the eicosanoids (see below).

The omega-3 fatty acid ALA (18:3n-3) can be converted to the long-chain omega-3 fatty acid, eicosapentaenoic acid (EPA; 20:5n-3). EPA can be elongated to docosapentaenoic acid (DPA 22:5n-3), which is further elongated, desaturated, and beta-oxidized to produce docosahexaenoic acid (DHA; 22:6n-3). EPA and DHA are also precursors of several classes of eicosanoids and docosanoids, respectively, are known to play several other critical roles, some of which are discussed further below.

The conversion from parent fatty acids into the VLC PUFAs - EPA, DHA, and AA - appears to occur slowly in humans. In addition, the regulation of conversion is not well understood, although it is known that ALA and LA compete for entry into the metabolic pathways.

Physiological Functions of EPA and AA

As stated earlier, fatty acids play a variety of physiological roles. The specific biological functions of a fatty acid are determined by the number and position of double bonds and the length of the acyl chain.

Both EPA (20:5n-3) and AA (20:4n-6) are precursors for the formation of a family of hormone-like agents called eicosanoids. Eicosanoids are rudimentary hormones or regulatory molecules that appear to occur in most forms of life. However, unlike endocrine hormones, which travel in the blood stream to exert their effects at distant sites, the eicosanoids are autocrine or paracrine factors, which exert their effects locally - in the cells that synthesize them or adjacent cells. Processes affected include the movement of calcium and other substances into and out of cells, relaxation and contraction of muscles, inhibition and promotion of clotting, regulation of secretions including digestive juices and hormones, and control of fertility, cell division, and growth.³

Figure 1.1

EPA (0522:6 n-3) also affects lipoprotein metabolism and decreases the production of substances - including cytokines, interleukin 1β (IL-1β), and tumor necrosis factor α (TNF-α) - that have pro-inflammatory effects (such as stimulation of collagenase synthesis and the expression of adhesion molecules necessary for leukocyte extravasation [movement from the circulatory system into tissues]).² DPA (22:5n-3), the elongation product of EPA, is metabolized to DHA (22:6n-3). DHA (22:6n-3) is the precursor to a newly-described metabolite called 10,17S-docosatriene,⁴ which is part of a family of compounds called ‘resolvins.’⁵ They are in the brain in response to an ischemic insult and counteract the pro-inflammatory actions of infiltrating leukocytes by blocking interleukin 1-beta-induced NF-kappaB activation and cyclooxygenase-2 expression.⁶ DHA also plays a role in retinal rod outer segments by influencing membrane fluidity so as to optimize G protein coupled signaling.⁷ The mechanism responsible for the suppression of cytokine production by omega-3 LC PUFAs and VLCPUFAs remains unknown, although suppression of omega-6-derived eicosanoid production by omega-3 fatty acids may be involved, because the omega-3 and omega-6 fatty acids compete for common enzymes in the fatty acid metabolic pathway, including delta-6 desaturase, as well as the rate-limiting enzymes in the eicosanoid pathway - phospholipases A2, cyclooxygenase, and lipoxygenase.

DPA (22:5n-3) (the elongation product of EPA) and its metabolite DHA (22:6n-3) are frequently referred to as very long chain n-3 fatty acids (VLCFA). Along with AA, DHA is the major PUFA found in the brain and is thought to be important for brain development and function. Recent research has focused on this role and the effect of supplementing infant formula with DHA (since DHA is naturally present in human breast milk but not in formula).

Dietary Sources and Requirements

Table 1.2 Sources and proportions of omega-3 fatty (more...)

Table 1.2 Sources and proportions of omega-3 fatty acids in common foods and supplements

Food/supplement	EPA	DHA	DPA	ALA
	20:5n-3	22:6n-3	22:5n-3	18:3n-3
Food/Supplement in which Total Omega-3 Fatty Acids account for more than 50% of Total PUFA
Fish
Anchovy
Halibut
Herring
Mackerel
Salmon
Sardine
Tuna
Canned, water packed
Fresh Bluefin
Oils/Supplements
Cod liver oils
Coromega*
Fish oil capsules*
Flaxseed/linseed oil*
Herring oil
MaxEPA*
Menhaden oil
Neuromins*
Omacor*
Ropufa*
Salmon oil
Sardine oil
Seeds and other foods
Flaxseeds/Linseeds
Spinach, cooked
Foods/Supplements in which total Omega 3 fatty acids are 10–50% of total PUFA
Oils
Black currant oil
Canola oil†
Mustard seed oils
Soybean oil
Walnut oil
Wheat germ oil
Other foods
Wheat germ
Human milk‡
Foods/Supplements in which total omega 3 fatty acids are less than 10% of total PUFA
Efamol Marine*
Peanut butter
Soybeans
Olive oil
Walnuts

*

Dietary Supplement;

† Also called rapeseed oil;

‡ The amounts of ALA, EPA, and DHA in human milk vary greatly as a function of maternal diet; the amount of DHA rarely seems to exceed 25 percent of the total n-3 PUFA content (ALA is present in the greatest amount), but that content as well as the proportion of DHA is assumed to meet the requirements of the infant.

Table 1.3 Good food sources* of omega-3 fatty acids (more...)

Table 1.3 Good food sources* of omega-3 fatty acids

	EPA+DHA	ALA		EPA+DHA	ALA
Fish (3oz. Cooked)			Oils (1 Tbs.)
Anchovy			Canola
Halibut			Cod liver
Herring, Atlantic			Flaxseed/linseed
Pacific			Herring
Mackerel, Atlantic			Menhaden
Pacific			Salmon
Salmon, Atlantic†			Sardine
Sardines			Soybean
Trout, Rainbow			Walnut
Tuna, Albacore			Wheat germ
Canned light, water-packed
Canned white, water-packed
Fresh Bluefin
Organ Meats (3 oz. Cooked)			Seeds
Brain, lamb			Flaxseeds/linseeds (1 Tbs.)
Brain, pork
Thymus, calf
Other Foods
Caviar (1 oz.) ‡
Human breast milk (1c) ‡	§
Soybeans, cooked (1/2c)
Spinach, cooked (1/2c)
Tofu, regular (1/2c)
Walnuts (1/4c)
Wheat germ (1/4c) ‡

Source: Figures adapted from USDA, 2003;

9

Foods that provide (per serving) 10 percent or more of the Adequate Intake (AI) for ALA or the Acceptable Macronutrient Distribution Range (AMDR) for EPA and DHA (10 percent of the AMDR for ALA); an AI is a recommended average daily intake level based on observed or experimentally determined estimates of nutrient intake by a group of apparently healthy people (thus, assumed to be adequate) when an RDA cannot be determined; an AMDR is defined as “a range of intakes for a particular energy source that is associated with reduced risk of chronic disease while providing adequate intake of essential nutrients.”;

† Farm-raised Atlantic salmon have nearly identical omega-3 fatty acid levels to wild Atlantic salmon and significantly more omega-3 fatty acids than wild Pacific salmon;

‡ Standard serving size not established;

§ See table note for Table 1.2.

Table 1.4 Estimates of the mean intake of LA, ALA, (more...)

Table 1.4 Estimates of the mean intake of LA, ALA, EPA, and DHA in the U.S. Population from analysis of NHANES III data.*

	Grams/day		Percent energy intake/day
	Mean ± SEM	Median (range)†	Mean ± SEM	Median (range)†
LA (18:2n-6)	14.1 ± 0.2	9.9 (0 – 168)	5.79 ± 0.05	5.30 (0 – 39.4)
ALA (18:3n-3)	1.33 ± 0.02	0.90 (0 – 17)	0.55 ± 0.004	0.48 (0 – 4.98)
EPA (20:5n-3)	0.04 ± 0.003	0.00 (0 – 4.1)	0.02 ± 0.001	0.00 (0 – 0.61)
DHA (22:6n-3)	0.07 ± 0.004	0.00 (0 – 7.8)	0.03 ± 0.002	0.00 (0 – 2.86)

*

Based on analysis of a single 24-hour dietary recall from NHANES III data;

† Distributions are not adjusted for the over-sampling of Mexican -Americans, non-Hispanic African Americans, children five years old and under, and adults 60 years and over in the NHANES III dataset.

Table 1.5 Mean, range, and median usual daily Intakes (more...)

Table 1.5 Mean, range, and median usual daily Intakes (ranges) of n-6 and n-3 PUFAs, in the U.S. population, from analysis of CSFII data (1994 to 1998).*

	Mean (gms/d) (± SEM)†	Range of Means (gms/d) (±SEM)	Median (gms/d) (± SEM)†
LA (18:2n-6)	13.0 ± 0.1	6.7 ± 0.1–17.6 ± 0.5	12.0 ± 0.1
Total n-3 FA	1.40 ± 0.01	0.72 ± 0.02 – 1.86 ± 0.04	1.30 ± 0.01
ALA (18:3n-3)	1.30 ± 0.01	0.72 ± 0.02 – 1.73 ± 0.04	1.21 ± 0.01
EPA (20:5n-3)	0.028	0.002 – 0.049	0.004
DPA (22:5n-3)	0.013	0.001 – 0.019	0.005
DHA (22:6n-3)	0.057 ± 0.018	< 0.0005 ± 0.001	0.046 ± 0.013

9

Source: Adapted from Dietary Reference Intakes Report;

*

Estimates are based on respondents' intakes on the first day of survey and were adjusted using the Iowa State University method;

† For all individuals.

Lacking sufficient evidence from research on the effects or correction of dietary deficiencies to establish Recommended Dietary Allowances (RDAs) for the essential fatty acids, the Food and Nutrition Board (FNB) of the Institute of Medicine⁹ has set adequate intakesⁱⁱ (AI) for the essential fatty acids, based on the average intakes of healthy CSFII participants. The AIs for the essential fatty acids vary by age group and sex, as well as for particular conditions such as pregnancy and breastfeeding. For ALA, the AI for men 19 and older, is 1.6 grams/day and the AI for (non-pregnant, non-breastfeeding) women is 1.1 grams/day. The AI for LA is 17 grams/day for men and 11 grams/day for women.

Table 1.6 The omega-3 fatty acid content, in grams (more...)

Table 1.6 The omega-3 fatty acid content, in grams per 100 g food serving, of a representative sample of commonly consumed fish, shellfish, fish oils, nuts and seeds, and plant oils.*

Food item	EPA	DHA	ALA
Fish (Cooked in dry heat unless otherwise specified)
Anchovy, European	0.8	1.3	-
Bass, Freshwater, Mixed Sp.	0.3	0.5	0.1
Bass, Striped	0.2	0.8	trace
Bluefish	0.3	0.7	-
Carp	0.3	0.3	0.3
Catfish, Channel, farmed	trace	0.1	0.1
Cod, Atlantic	trace	0.2	trace
Cod, Pacific	0.1	0.2	trace
Eel, Mixed Sp.	0.1	0.1	0.6
Flounder & Sole Sp.	0.2	0.3	trace
Grouper, Mixed Sp.	trace	0.2	-
Haddock	0.1	0.2	trace
Halibut, Atlantic and Pacific	0.1	0.4	0.1
Halibut, Greenland	0.7	0.5	0.1
Herring, Atlantic	0.9	1.1	0.1
Herring, Pacific	1.2	0.9	0.1
Mackerel, Atlantic	0.5	0.7	0.1
Mackerel, Pacific and Jack	0.7	1.2	0.1
Mullet, Striped	0.2	0.1	trace
Ocean Perch, Atlantic	0.1	0.3	0.1
Pike, Northern	trace	0.1	trace
Pike, Walleye	0.1	0.3	trace
Pollock, Atlantic	0.1	0.5	-
Pompano, Florida	0.2	0.5	-
Roughy, Orange	trace	-	trace
Salmon, Atlantic, Farmed	0.7	1.5	0.1
Salmon, Atlantic, Wild	0.4	1.4	0.4
Salmon, Chinook	1.0	0.7	0.1
Salmon, Chinook, Smoked(lox)	0.2	0.3	-
Salmon, Chum	0.3	0.5	trace
Salmon, Coho, Farmed	0.4	0.9	0.1
Salmon, Coho, Wild	0.4	0.7	0.1
Salmon, Pink	0.4	0.6	trace
Salmon, Pink, Canned	0.8	0.8	0.1
Salmon, Sockeye	0.5	0.7	0.1
Sardine, Atlantic, Canned in Oil	0.5	0.5	0.5
Sea bass, Mixed Sp.	0.2	0.6	-
Seatrout, Mixed Sp.	0.2	0.3	trace
Shark, Mixed Sp., battered and fried	0.3	0.4	0.2
Snapper, Mixed Sp.	0.1	0.3	0.1
Swordfish	0.1	0.7	0.2
Trout, Mixed Sp.	0.3	0.7	0.2
Trout, Rainbow, Farmed	0.3	0.8	0.1
Trout, Rainbow, Wild	0.5	0.5	0.2
Tuna, Fresh, Bluefin	0.4	1.1	-
Tuna, Fresh, Skipjack	trace	0.2	-
Tuna, Fresh, Yellowfin	trace	0.2	trace
Tuna, Light, Canned in Oil	trace	0.1	trace
Tuna, Light, Canned in Water	trace	0.2	trace
Tuna, White, Canned in Oil	trace	0.2	0.2
Tuna, White, Canned in Water	0.2	0.6	trace
Whitefish, Mixed Sp.	0.4	1.2	0.2
Whitefish, Mixed Sp., Smoked	trace	0.2	-
Wolf fish, Atlantic	0.4	0.4	trace
Shellfish (Raw)
Abalone, Mixed Sp., fried	0.1	0.1	0.1
Clam, Mixed Sp., moist heat	0.1	0.1	trace
Crab, Alaska King, moist heat	0.3	0.1	-
Crab, Blue, moist heat	0.2	0.2	-
Crayfish, Mixed Sp., Farmed	0.1	trace	trace
Lobster, Northern, moist heat	0.1	trace	trace
Mussel, Blue	0.3	0.5	trace
Oyster, Eastern, Farmed	0.2	0.2	0.1
Oyster, Eastern, Wild	0.3	0.3	0.1
Oyster, Pacific	0.9	0.5	0.1
Scallop, Mixed Sp.	0.2	0.2	-
Shrimp, Mixed Sp.	0.2	0.1	trace
Squid, Mixed Sp., fried	0.2	0.4	0.1
Fish Oils
Cod Liver Oil	6.9	11.0	0.9
Herring Oil	6.3	4.2	0.8
Menhaden Oil	13.2	8.6	1.5
Salmon Oil	13.0	18.2	1.1
Sardine Oil	10.1	10.7	1.3
Nuts and Seeds
Butternuts, Dried	-	-	8.7
Flaxseed			18.1
Walnuts, English	-	-	9.1
Plant Oils
Canola (Rapeseed)	-	-	9.3
Flaxseed Oil	-	-	53.3
Soybean Lecithin Oil	-	-	5.1
Soybean Oil	-	-	6.8
Walnut Oil	-	-	10.4
Wheatgerm Oil	-	-	6.9

Source: Figures adapted from USDA, 2003;

*

Sp = species.

Physiological Role of Omega-3 Fatty Acids in the Brain

Figure 1.2 Schematic diagram illustrating the role (more...)

   Figure 1.2 Schematic diagram illustrating the role of the metabolism of the essential fatty acids in neuronal signal transduction

Figure 1.2

Work in animal models has reported superior learning and memory in animals fed omega-3 fatty acids compared with control animals.^{17, 18} In transgenic mouse models, dietary DHA improved memory, increased synapse density and decreased amyloid beta toxicity, thus providing evidence of protection against AD and cognitive decline.^{19, 20}

Omega-3 Fatty Acids in Neurologic Disorders

Deficiencies in omega-3 FA and/or an imbalance in the ratio of omega-6 FA to omega-3 FA have been implicated in a variety of disorders affecting the CNS, including Alzheimer's disease (AD),^21–26 the peroxisomal biogenesis disorders (a collection of relatively rare neurological conditions, of which Zellweger's syndrome is one of the most common),^27–32 several psychiatric disorders,^{9, 11, 13, 33} Parkinson's disease,^{34, 35} amyotrophic lateral sclerosis (ALS),³⁶ Huntington's disease,^37–39 ischemic brain injury,³⁶ and multiple sclerosis (MS).^40–49 Indeed, dietary intake of omega-3 FA has been associated with a reduced incidence of MS since the early studies of Swank in the 1950s.⁵⁰

Various animal and human studies have suggested several possible biological mechanisms for the role of FA in disease processes. Evidence for a positive association between intake of omega-3 FA and reduction of cardiovascular risk and adverse outcomes,⁵¹ along with the finding that certain forms of dementia have been related to cardiovascular risk factors, suggest that one mechanism linking FA and cognitive function or dementia may be atherosclerosis and thrombotic events.⁵² Inflammation is another mechanism that may explain the role that omega-3 fatty acids play in dementia.⁵³

Several intervention trials in human infants have investigated the effects of omega-3 FA on cognitive development.^{50, 54} Research has also shown these FA to be important in human infant visual development. A meta-analysis of several intervention trials showed that healthy pre-term infants who were administered DHA-supplemented formula had significantly higher visual resolution acuity at two and four months of age compared with infants fed DHA-free formula.⁵⁵

However, few clinical intervention trials have examined the role of omega-3 FA in changes in cognitive function with aging and adult neurological conditions. The studies that have investigated the relationship between omega-3 FA intake and cognitive function, dementia, or other neurological diseases are mainly observational.

Rationale for and Organization of this Report

Epidemiological studies have suggested that groups of people who consume diets high in omega-3 FAs may experience a lower prevalence of certain neurological conditions, particularly cognitive impairment and dementia disorders. In addition, several studies have attempted to assess the effects of adding omega-3 FA to the diet, either as omega-3 FA-rich foods or as dietary supplements (primarily fish oils) in the treatment of certain neurological diseases, notably MS.

In response to this evidence, a number of omega-3 FA-containing dietary supplements that claim to protect against a variety of conditions have appeared on the market. Thus, AHRQ and the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) have requested a synthesis of the research to date on the health effects of diets rich in omega-3 FA.

The remainder of this report is organized into four chapters. Chapter Two describes the methods we used to identify and review studies related to the role of omega-3 FA in cognitive function with aging, dementia, and other neurological diseases/conditions. We did not analyze any studies on the role of omega-3 fatty acids in stroke because this topic has been addressed by the New England EPC in their report on Effects of Omega-3 Fatty Acids on Cardiovascular Disease. Chapter Three presents our findings related to the effects of omega-3 FA on those diseases/conditions. Chapter Four presents our conclusions and recommendations for future research in this area.

Objectives

The topic of this report was nominated by the NIH ODS. The three participating Evidence-Based Practice Centers (EPCs) were asked to examine the effects of omega-3 fatty acids, in general, and on the following conditions: Cardiovascular Disease, Transplantation, Immune-Mediated Diseases, Gastrointestinal/Renal Diseases, Cancer, Neurological conditions, Asthma, Child/Maternal Health, Eye Health, and Mental Health. The Southern California EPC (SCEPC) was responsible for examining Immune-Mediated Diseases and Gastrointestinal/Renal Diseases in Year-one of the project and Cancer and Neurological conditions in Year-two of the project.

Scope of Work

The methodology that we used for this study included the following:

• Refining the preliminary questions provided by AHRQ,

• Convening a technical expert panel to advise the SCEPC on the study,

• Identifying sources of evidence in the scientific literature,

• Establishing inclusion/exclusion criteria for the studies identified in the scientific literature,

• Identifying potential evidence with attention to controlled clinical trials using omega-3 fatty acids,

• Evaluating potential evidence for methodological quality and relevance,

• Extracting data from studies meeting methodological and clinical criteria,

• Synthesizing the results,

• Performing further statistical analysis on selected studies, as appropriate,

• Performing meta-analyses where appropriate,

• Submitting the results to technical experts for peer review,

• Incorporating reviewers' comments into a final report for submission to AHRQ.

Original Proposed Key Questions

Preliminary questions for the project were developed by ODS in collaboration with the following NIH Institutes: (a) National Cancer Institute (NCI); (b) National Eye Institute (NEI); (c) National Heart, Lung, and Blood Institute (NHLBI); (d) National Institute of Alcohol Abuse and Alcoholism (NIAAA); (e) National Institute of Allergy and Infectious Diseases (NIAID); (f) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); (g) National Institute of Child Health and Human Development (NICHD); (h) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); (i) National Institute of Mental Health; and (j) National Institute of Neurological Disorders and Stroke (NINDS). The general and disease-specific questions that were originally proposed are detailed in Appendix A.1.

Technical Expert Panel

Each AHRQ evidence report is guided by a Technical Expert Panel (TEP). The TEP advises the SCEPC on refining the preliminary questions, determining the proper inclusion/exclusion criteria for the studies, determining populations of interest, establishing proper outcome measures, and conducting appropriate analyses.

We convened a TEP that focused on neurological diseases and conditions. The TEP was composed of distinguished basic scientists and clinicians, with established expertise in omega-3 FA, human nutrition, dietary assessment methods, and neurology. In addition to the experts that we identified, AHRQ and the NIH Institute of Neurological Disorders and Stroke (NINDS) and Institute on Aging (NIA) recommended a number of industry experts. The members of our technical expert panel are listed by name along with a summary of their key comments and recommendations in Appendix A.2.

Key Questions Addressed in this Report

Based on input from our TEP, the preliminary disease-specific questions were revised. The questions that are addressed in this report are as follows:

• What is the evidence that omega-3 fatty acids play a role in maintaining cognitive function in normal aging?

• What is the evidence that omega-3 fatty acids affect the incidence of dementia including Alzheimer's disease?

• What is the evidence that omega-3 fatty acids are effective in the treatment of dementia including Alzheimer's disease?

• What is the evidence that omega-3 fatty acids affect the incidence of neurological diseases?

• What is the evidence that omega-3 fatty acids prevent the progression of multiple sclerosis?

Identification of Literature Sources

Potential evidence for our study came from three sources: on-line library databases, the reference lists of all relevant articles, and industry experts.

Jessie McGowan, Senior Information Scientist, and Nancy Santesso, Knowledge Translation Specialist, at the University of Ottawa were responsible for developing a common search strategy for omega-3 FA for the 3 participating EPCs. Nancy Santesso developed a core omega-3 search strategy in collaboration with project librarians, biochemists, nutritionists, and clinicians, who also provided biochemical names, abbreviations, food sources, and commercial product names for omega-3 FA. The literature search was not restricted by language of publication or by study design, in order to increase sensitivity. When possible, the searches were limited to studies involving human subjects. The core search strategy is detailed in Appendix A.4.

For the SCEPC, this core search strategy was incorporated into a search for cognitive function with aging, Alzheimer's disease, and other neurological diseases/conditions. The strategy for this search is detailed in Appendix A.4.

The following databases were searched: Medline (1966-2003), Premedline (December, 2003), Embase (1980-2003), Cochrane Central Register of Controlled Trials (4th Quarter, 2003), CAB Health (1973-2003), Dissertation Abstracts (1861-2003). All of these databases were searched using the Ovid interface, except CAB Health, which was searched through SilverPlatter. Any duplicate records were identified and removed within each search question using Reference Manager software. The citations obtained from these literature searches were sent to the SCEPC via e-mail.

Two experienced reviewers, Walter Mojica and Amalia Issa, who were blinded to study authors and sources independently evaluated the citations and corresponding abstracts, if available. The reviewers selected article titles that focused on omega-3 FA and normal cognitive function with aging, dementia, and other neurologic diseases/conditions. In addition, they selected article titles that pertained to the disease conditions of the other participating EPCs. Language was not a barrier to inclusion. Articles that either reviewer selected were ordered, as well as those articles whose relevance could not be determined from the title or abstract. The articles were ordered from the UCLA library, or Infotrieve, a Los Angeles-based literature retrieval firm with contacts around the world. The literature was tracked using ProCite and Access software.

In addition, we sent letters to industry experts recommended by the ODS to obtain any unpublished data (Figure A.3.1).

Evaluation of Evidence

Extraction of Data

For the studies that passed our screening criteria, two reviewers independently abstracted detailed data onto a specialized quality review form (QRF) (Figure B.2, Appendix B).

Walter Mojica and Amalia Issa independently reviewed all of the studies. The reviewers resolved differences through consensus, and a senior physician researcher, Catherine MacLean, resolved any disagreements that could not be resolved through this method.

The QRF included questions about the study design; the outcomes of interest; study sample characteristics; details on the intervention, such as the dose, frequency, and duration; adverse events; the elapsed time between the intervention and outcome measurements, and, the types of outcome measures.

We consulted with several outside scientists to complete QRFs for foreign-language articles. Foreign language articles were reviewed as follows. Spanish-language articles were reviewed by Walter Mojica, French-language articles by Amalia Issa who are fluent in these languages. For other foreign-language articles, a single reviewer who is fluent in the language worked with Catherine MacLean to complete the standard abstraction form.

Grading Evidence

Data Synthesis

Because too few studies were identified to perform pooled analyses (meta-analysis), we performed a qualitative synthesis of the evidence.

This report is organized by five different study questions. For each study question we describe the number and design of studies identified that pertained to the question and describe the overall effect of omega-3 fatty acids across the studies. We describe the unit of analysis for omega-3 consumption, i.e. fish, total omega-3, DHA, EPA or ALA. We summarized the point estimates and statistical testing that were described in the original studies and state when these parameters were not reported. We specifically comment on whether the studies assessed the effects of omega-3 fatty acids on sub-populations, the effects of covariates on outcomes, the effects of omega-3 fatty acid source, dose and exposure duration and sustainment of effect after treatment with omega-3 fatty acids. When these parameters were assessed they were described. We also describe the quality and applicability of the studies for each topic. Of note, we describe whether information on covariates was reported in two ways and for two reasons. First, we report whether covariates had a specific effect on the outcome of interest and the magnitude of the effect if it was significant. Second, we report whether there was adjustment for covariates as a measure of methodologic quality.

Peer Review

Results of Literature Search

Figure 3.1 Literature Flow

   Figure 3.1 Literature Flow

Figure 3.1

Figure 3.1

Effects of Omega-3 Fatty Acids

Summaries of all evaluated neurological studies can be found in Appendix C (Tables C.1 through C.4).

Cognitive Function in Normal Aging

Table 3.1 Risk of cognitive impairment or decline in (more...)

Table 3.1 Risk of cognitive impairment or decline in normal aging reported in a cohort study with consumption of omega-3 fatty acids, by categorization of omega-3 fatty acid intake.*

Author, Year	Outcome	Study arm (quartile, quintile or dose group)	n	Amount	Estimates of effect
Cohort					Age-adjusted OR (95% CI)		Multivariable RR (95% CI)		Multivariable Adjustors
Fish
Kalmijn, 199759	Cognitive impairment	None	NR	none	1.0		1.0		Age, education, cigarette smoking, alcohol consumption, energy intake, baseline MMSE score.
Zutphen Elderly Study		High	NR	> 0–20 g/day	0.43	(0.23–0.78)	0.63	(0.33–1.21)
		Total 476				p = 0.004‡		p = 0.13‡
	Cognitive decline	None	NR	none	NR		1.0
		High	NR	> 0–20 g/day	NR		0.45	(0.17–1.16)
		Total 342						p = 0.09‡
Omega-3 fatty acids†
Kalmijn, 199759	Cognitive impairment	Low	NR	0–37.5 mg/day	1.00		NR		Age, education, cigarette smoking, alcohol consumption, energy intake, baseline MMSE score.
Zutphen Elderly Study		Medium	NR	37.5–155.5 mg/day	1.09	(0.65–1.80)	NR
		High	NR	155.5–2,110.5 mg/d	0.96	(0.57–1.62)	NR
		Total 476				p = 0.9‡
	Cognitive decline	Low	NR	0–37.5 mg/day	1.00	NR	NR
		Medium	NR	37.5–155.5 mg/day	0.85	(0.40–1.82)	NR
		High	NR	155.5–2,110.5 mg/d	0.78	(0.35–1.73)	NR
		Total 342				p=0.5

*

NR= not reported;

† EPA and DHA;

‡ test for trend.

Overall effect. We identified one study that evaluated the effect of omega-3 FA on cognitive function in community-dwelling elderly persons. This study⁵⁹ investigated the association between omega-3 FA and cognitive function in a cohort of 818 community-dwelling men (ranging in age from 64 to 84 years old) living in the Dutch town of Zutphen, who were participants in the Zutphen Elderly Study, a longitudinal study on risk factors for various chronic diseases. Data about dietary intake were collected by trained interviewers in 1985, 1990, and 1993, and data about cognitive function were collected in 1990 and 1993. Complete dietary information was collected on 476 men, and complete information regarding cognitive function was collected on 342 men. The relationship between both fish consumption and total omega-3 fatty acid consumption and both cognitive impairment and cognitive decline were assessed. Cognitive impairment was defined as a MMSE score ≤ 25; cognitive decline was defined as a drop of more than two points in the MMSE over a 3-year period, which corresponds to the 15^th percentile of change. Compared with no fish consumption, fish consumption was inversely associated with cognitive impairment in crude analyses, but not after adjustment for multiple variables (Table 3.1). Fish consumption was also inversely associated with development of cognitive decline, though not significantly so (Table 3.1). Total omega-3 fatty acid consumption was not related to cognitive impairment or cognitive decline (Table 3.1).

Sub-populations. This study did not evaluate the differential effects of omega-3 FA on distinct subpopulations.

Covariates. Although analyses adjusted for a number of different covariates in a multivariable regression model (Table 3.1), the effects of specific covariates on the association between omega-3 fatty acid consumption and cognitive function were not described.

Effects of source, dose, and exposure duration

Source: This study assessed omega-3 fatty acid effects in terms of fish consumption and total omega-3 fatty acid consumption. Fish consumption was associated with a reduced risk of cognitive impairment but had no association with cognitive decline; omega-3 fatty acid consumption was not associated with either outcome.

Dose: Dose effect was not assessed for fish. A dose effect was observed for omega-3 fatty acid consumption and cognitive impairment on unadjusted analyses (p for trend = 0.9), but not on adjusted analyses. No dose effect was found with omega-3 fatty acid consumption and cognitive decline.

Exposure Duration: Effects of exposure duration were not assessed.

Sustainment of Effect. Sustainment of effect was not reported.

Quality and Applicability. Parameters of methodologic quality are as follows:

This study adjusted for confounders, had valid ascertainment of exposures and outcomes, ascertained that exposure occurred before outcome measurement, and described withdrawals and drop outs. It did not blind to exposure/outcome and did not describe selection bias.

This study had an applicability rating of II because the population sampled included only males. Thus, although this study represented a relevant sub-group of the target population, it was not representative of the entire target population because of its exclusive sampling of one gender.

Incidence of Dementia

Table 3.2 Risk of dementia reported in prospective (more...)

Table 3.2 Risk of dementia reported in prospective cohort studies for different categories of consumption of omega-3 fatty acids, by category of consumption.*

Author, Year	Type of dementia	Study arm (quartile, quintile or dose group)	Total n	No. of Cases	Amount by category	Estimates of effect
Cohort						Age adjusted RR (95% CI)		Multivariable adjusted RR (95% CI)		Multivariable Adjustors
FISH
Barberger-Gateau, 200221	Dementia	1	NR	NR	NR	1.0		1.0		Age, sex, education
PAQUID (Personnes Agées QUID) Study		2	1122	124	At least once a week	0.66†	(0.47–0.93)	0.73†	(0.52–1.03)
	Alzheimer's disease	1	NR	NR	NR	1.0		NR
		2	1122	99	At least once a week	0.69†	(0.47–1.01)	NR
		Total 1122		223
Kalmijn, 199767	Total dementia	1	1807	58	≤ 3 g/day	NR		1.0		Age, sex, education, total energy intake.
Rotterdam Study		2	1773	58	3.0–18.5 g/day	NR		0.8	(0.4–1.4)
		3	1806	58	> 18.5 g/day	NR		0.4	(0.2–0.9)
				58					p = 0.03‡
	Alzheimer's disease without vascular component	1	1807	37	≤ 3 g/day	NR		1.0
		2	1773	37	3.0–18.5 g/day	NR		0.9	(0.4–1.8)
		3	1806	37	> 18.5 g/day	NR		0.3	(0.1–0.9)
				37					p = 0.005‡
	Dementia with a vascular component	1	1807	12	≤ 3 g/day	NR		1.0
		2	1773	12	3.0–18.5 g/day	NR		0.6	(0.2–2.5)
		3	1806	12	> 18.5 g/day	NR		0.7	(0.2–2.8)
		Total 5386		12					p = 0.39‡
Morris, 200323	Alzheimer's disease	1	121	32	never	1.0		1.0		Age, sex, race, education, vitamin E intake, other fat intake, cardiovascular disease, APO-ε 4 status.
Chicago Health and Aging Project		2	250	39	1–3 servings/ month	0.7	(0.3–1.6)	0.6	(0.3–1.3)
		3	296	43	1 serving/ week	0.5	(0.2–1.0)	0.4	(0.2–0.9)
		4	148	26	≥ 2 servings/week	0.6	(0.2–0.9)	0.4	(0.2–0.9)
		Total 815		140			p = 0.18‡		p = 0.07‡
Omega-3 fatty acids
Morris, 200323	Alzheimer's disease	1	NR	32	0.9 g/day	1.0		1.0		Age, sex, race, education, vitamin E intake, other fat intake, cardiovascular disease, APO-ε 4 status.
Chicago Health and Aging Project		2	NR	30	1.13 g/day	1.1	(0.4–2.9)	1.2	(0.5–3.0)
		3	NR	22	1.30 g/day	0.5	(0.2–1.4)	0.6	(0.2–1.7)
		4	NR	24	1.49 g/day	0.6	(0.2–1.5)	0.7	(0.3–1.6)
		5	NR	23	1.75 g/day	0.3	(0.1–0.7)	0.4	(0.1–0.9)
		Total 815		131			p = 0.01‡		p = 0.01‡
ALA
Morris, 200323	Alzheimer's disease	1	NR	26	0.72 g/day	1.0		1.0		Age, sex, race, education, vitamin E intake, other fat intake, cardiovascular disease, APO-ε 4 status.
Chicago Health and Aging Project		2	NR	33	0.92g/day	1.7	(0.7–3.8)	1.8	(0.8–3.8)
		3	NR	24	1.06g/day	0.8	(0.4–1.9)	0.8	(0.4–2.0)
		4	NR	25	1.23g/day	0.8	(0.4–1.7)	0.9	(0.4–2.0)
		5	NR	23	1.46g/day	0.5	(0.2–1.1)	0.7	(0.3–1.6)
		Total 815		131			p = 0.01‡		p = 0.10‡
DHA
Morris, 2003 23	Alzheimer's disease	1	NR	28	0.03 g/day	1.0		1.0		Age, sex, race, education, vitamin E intake, other fat intake, cardiovascular disease, APO-ε 4 status.
Chicago Health and Aging Project		2	NR	45	0.05 g/day	0.8	(0.3–2.1)	0.8	(0.3–2.1)
		3	NR	14	0.06 g/day	0.4	(0.1–1.1)	0.4	(0.1–1.0)
		4	NR	19	0.07 g/day	0.3	(0.1–0.9)	0.2	(0.1–0.8)
		5	NR	25	0.10 g/day	0.4	(0.2–1.1)	0.3	(0.1–0.9)
		Total 815		131			p = 0.05‡		p = 0.02‡
EPA
Morris, 2003 23	Alzheimer's disease	1	NR	55	0.0 g/day	1.0		1.0		Age, sex, race, education, vitamin E intake, other fat intake, cardiovascular disease, APO-ε 4 status.
Chicago Health and Aging Project		2	NR	NR§	0.0 g/day	NR§	NR§	NR§	NR§
		3	NR	35	0.01 g/day	1.0	(0.4–2.4)	1.1	(0.4–2.8)
		4	NR	14	0.02 g/day	0.5	(0.2–1.2)	0.5	(0.2–1.2)
		5	NR	27	0.03 g/day	0.9	(0.4–2.1)	0.9	(0.4–2.3)
		Total 815		131			p = 0.40‡		p = 0.40‡

*

NR = not reported, g = grams;

† hazard ratio;

‡ age and sex adjusted; test for trend;

§ Authors report that 40% of participants had 0 g/day of intake.

Overall effect. We identified three prospective cohort studies^{21, 23, 67} that evaluated the effect of omega-3 FA on the incidence of dementia (Table 3.2). All three of the studies assessed the incidence of dementia relative to fish consumption; one also assessed risk relative to total omega-3 fatty consumption and relative to consumption of ALA, EPA, and DHA, individually.²³ Fish intake was associated with a significant reduction in the incidence of non-Alzheimer's dementia in all three studies,^{21, 67} although in one,²¹ statistical significance was barely lost with multivariable adjustment²¹ (Table 3.2). Fish consumption was associated with a reduced risk of Alzheimer's dementia in all three of the studies; the association was statistically significant in one⁶⁷ and nearly so in the other two^{21, 23} (Table 3.2). Total omega-3 fatty acid consumption and consumption of DHA were associated with a significant reduction in the incidence of Alzheimer's disease; consumption of ALA and EPA were not²³ (Table 3.2).

Sub-populations. One study assessed whether gender modified the effect of total omega-3 fatty acid consumption or consumption of fish, ALA, EPA, or DHA.²³ Total intake of omega-3 fatty acids was protective in females only (p for interaction= 0.02); gender did not modify the effect of fish, ALA, EPA, or DHA.

Covariates. Two of the studies^{23, 67} assessed the influence of covariates on the effect of omega-3 FA on incidence of dementia.

In one study,²³ the multivariable relative risks for intakes of total omega-3 fatty acids, DHA, and EPA did not change when adjusted for vitamin E intake, other fat intake, and cardiovascular disease. In the same study, multivariable risks for intake of ALA were reported as approximately 1.0 with adjustment for vitamin E but not affected by adjustment for cardiovascular disease; intake of ALA was strongly protective among people with the APO-E-4 genotype (RR = 0.08 per natural log {milligram} increase in ALA, p = 0.02).

In the other study,⁶⁷ estimates of relative risk did not change with adjustment for cigarette smoking, alcohol consumption, fiber consumption, antioxidant intake, stroke, myocardial infarction, or serum total and high-density lipoprotein cholesterol.

Effects of source, dose, and exposure duration

Source: Fish consumption was associated with a significantly reduced risk of dementia in three of the studies.²¹ In the one study that assessed the effect of total omega-3 fat consumption, ALA, DHA, and EPA on the incidence of dementia, total omega-3 and DHA were associated with significant reduced risk in multivariable analyses; ALA and EPA were not.

Dose: Dose effects were observed for fish in one study⁶⁷ and for total omega-3 consumption and DHA in another²³ (p for trend <0.05 for each) (Table 3.2).

Exposure Duration: None of the studies addressed exposure duration.

Sustainment of effect. Sustainment of effect was not assessed in any of the studies.

Quality and applicability. Among these three studies, all adjusted for confounders, reported using valid methods to ascertain outcomes, and confirmed that the exposure occurred prior to the outcome.

One study did not describe a valid method to ascertain dietary intake²¹ (method used was not described). One of the studies explicitly described whether the investigators were blinded to information on exposure when obtaining data on outcome or on outcome when obtaining data on exposure.^{23, 34, 61}

Of the three studies, two^{23, 67} had an applicability rating of I (applicable to the general target population of adults). One study received an applicability rating of II because it was performed in France.²¹

Treatment of Dementia

Table 3.3 The effect of omega-3 fatty acids on the (more...)

Table 3.3 The effect of omega-3 fatty acids on the treatment of dementia in one randomized controlled trial stratified by outcome.*

Author, Year	Results
Terano, 199424	Total n	Before	After 3 months	After 6 months	After 12 months
Mean scores of HDS-R
Standard nursing home diet	10	16.3	16.7	16.7	15.3
Standard nursing home diet PLUS DHA 4.3 grams/day	10	17.2	20.6†	19.9†	20.2
Mean scores of MMSE
Standard nursing home diet	10	19.7	19.4	19.6†	19.1
Standard nursing home diet PLUS DHA 4.3 grams/day	10	20.1	21.3	22.2	21.9

*

HDS-R = Hasegawa's Dementia rating scale;

MMSE = Mini Mental Status Exam;

† p < 0.05 for comparisons between groups with paired t-test.

Overall effect. We identified one study²⁴ that assessed the efficacy of omega-3 FA as a treatment for dementia. This RCT assessed the effect of supplementation with DHA on cognitive function among 20 elderly nursing home residents with vascular dementia. Cognitive functioning was evaluated using Hasegawa's Dementia rating scale (HDS-R) and MMSE scores at baseline, and after 3, 6, and 12 months. Baseline Hasegawa's Dementia rating scale and MMSE scores were 15 to 22, consistent with mild to moderate dementia. HDS-R and MMSE scores improved in the DHA-treated group but not among patients who were not treated with DHA (Table 3.3). Comparisons between groups were significant at 3 and 6 months for the HDS-R and at 6 months for the MMSE.

Sub-populations. The study did not evaluate the differential effects of omega-3 FA on distinct subpopulations.

Covariates. The study did not evaluate covariates.

Effects of source, dose, and exposure duration

Source: The source assessed was DHA.

Dose: A single dose of 4.3 g of DHA was administered; dose effect was not assessed.

Exposure Duration: The duration of exposure was 12 months. Significant differences between study groups were observed after 3 months and after 6 months, but not after 12 months.

Sustainment of effect. Sustainment of effect was not assessed in either report.

Table 3.4 Relationship between methodologic quality (more...)

Table 3.4 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on treatment of dementia in randomized controlled trials (RCTs)

		Methodologic Quality
Applicability		A	B	C
	I
	II			Terano24
	III

Quality and applicability. Although this trial is described as randomized, the randomization is not described as double-blind, and there is no description regarding blinding or withdrawals/dropouts. The study²⁴ had an applicability rating of II with a summary quality score of C (Jadad score = 1; concealment of allocation was not reported); thus it can be considered of poor quality (Table 3.4).

Incidence of Neurological Diseases

Table 3.6 Risk of neurological diseases reported in (more...)

Table 3.6 Risk of neurological diseases reported in prospective cohort or case-control studies for different categories of consumption of fish, by disease.*

Disease	Author, Year		Study arm (quartile; quintile; dose group; case or control)	n†	Amount	Estimates of effect
	Study Design					Multivariable adjusted RR (95% CI)		Multivariable Adjustors,
								Matching parameters
Fish
Multiple sclerosis	Zhang, 200061		Dose Groups					Multivariable adjustors: Age, smoking (cigarettes/day), energy intake (quintiles), alcohol consumption
	Cohort Study: The Nurses' Health Study I and II		1	81	< 1/week	1.0		Matching: NA
			2	77	1–2.9/week	1.0	(0.8–1.4)
			3	37	3–4.9/week	0.9	(0.6–1.3)
									p = 0.79‡
Multiple sclerosis	Ghadirian, 1998,43	Men	Control	64	-	1.0		Multivariable adjustors: Total energy, body mass index
	Case control study		Case	61	-	1.08§	(0.84–1.40)	Matching: Age, sex, phone number
		Women	Control	138	-	1.0
			Case	136	-	0.83§	(0.69–1.00)
		All	Control	202	-	1.0
			Case	197	-	0.91§	(0.78–1.05)
Cerebral palsy	Petridou, 1998,60		Control	166	1/week	1.0		Multivariable adjustors: ‘Core’ variables|| plus total energy intake, body mass index
	Case control study		Case	58	1/week	0.63	(0.37–1.08)	Matching: Age, neighborhood or age, physician
Omega-3 fat from fish
Parkinson's Disease	Chen, 200334	Men	Quintiles					Multivariable adjustors: Age, smoking (cigarettes/day), energy intake (quintiles), alcohol consumption
	Cohort Study: Health Professional Follow-up Study and The Nurses' Health Study		1	NR	0.03 % of energy	1.0		Matching: NA
			2	NR	0.07% of energy	0.84	(0.52–1.37)
			3	NR	0.1% of energy	1.08	(0.69–1.69)
			4	NR	0.2% of energy	0.88	(0.55–1.40)
			5	NR	0.3 % of energy	0.99	(0.63–1.55)
			Total 47,331		p = 0.9‡
		Women	Quintiles
			1	NR	0.03 % of	1.0
			2	NR	0.05 % of energy	0.70	(0.41–1.19)
			3	NR	0.08 % of energy	0.76	(0.45–1.29)
			4	NR	0.1% of energy	0.75	(0.45–1.26)
			5	NR	0.2 % of energy	0.90	(0.55–1.47)
			Total 88,653				p = 0.9‡
		Pooled men and women	Quintiles
			1	NR	NR	1.0
			2	NR	NR	0.77	(0.54–1.11)
			3	NR	NR	0.93	(0.66–1.31)
			4	NR	NR	0.82	(0.58–1.16)
			5	NR	NR	0.94	(0.68–1.32)
			Total 135,894				p = 0.9‡
ALA
Multiple Sclerosis	Zhang, 200061		Groups					Multivariable adjustors: Age, smoking (cigarettes/day), energy intake (quintiles), alcohol consumption
	Cohort Study: The Nurses' Health Study I and II		1	NR	< 1% of energy	1.0		Matching: NA
			2	NR	≥ 1% of energy	0.3	(0.1–1.1)
Parkinson's Disease	Chen, 200334	Men	Quintiles					Multivariable adjustors: Age, smoking (cigarettes/day), energy intake (quintiles), alcohol consumption
	Cohort Study: Health Professional Follow-up Study and The Nurses' Health Study		1	NR	0.05 % of energy	1.0		Matching: NA
			2	NR	0.06% of energy	0.54	(0.34–0.87)
			3	NR	0.08% of energy	0.75	(0.49–1.15)
			4	NR	0.09% of energy	0.88	(0.58–1.32)
			5	NR	0.1 % of energy	0.69	(0.45–1.07)
			Total 47,331				p = 0.4‡
		Women	Quintiles
			1	NR	0.04 % of energy	1.0
			2	NR	0.06 % of energy	0.83	(0.51–1.34)
			3	NR	0.07 % of energy	0.71	(0.43–1.17)
			4	NR	0.09% of energy	0.68	(0.41–1.13)
			5	NR	0.1 % of energy	0.60	(0.35–1.01)
			Total 88,563				p = 0.04‡
		Pooled men and women	Quintiles
			1	NR	NR	1.0
			2	NR	NR	0.67	(0.47–0.93)
			3	NR	NR	0.73	(0.53–1.01)
			4	NR	NR	0.79	(0.57–1.09)
			5	NR	NR	0.65	(0.46–0.91)
			Total 135,894				p = 0.05‡
EPA
Parkinson's Disease	Chen, 200334	Men	Quintiles
	Cohort Study: Health Professional Follow-up Study and The Nurses' Health Study		1	NR	0.009 % of energy	1.0		Multivariable adjustors: Age, smoking (cigarettes/day), energy intake (quintiles), alcohol consumption
			2	NR	0.02 % of energy	0.77	(0.48–1.25)
			3	NR	0.04 % of energy	0.88	(0.56–1.39)
			4	NR	0.06 % of energy	0.92	(0.59–1.44)
			5	NR	0.1 % of energy	0.91	(0.59–1.42)
			Total 47,331				p = 0.9‡
		Women	Quintiles
			1	NR	0.007 % of energy	1.0
			2	NR	0.01 % of energy	0.67	(0.39–1.16)
			3	NR	0.02 % of energy	0.80	(0.48–1.34)
			4	NR	0.04 % of energy	0.74	(0.44–1.24)
			5	NR	0.07 % of energy	0.91	(0.56–1.49)
			Total 88,563				p = 0.8‡
		Pooled men and women	Quintiles
			1	NR	NR	1.0
			2	NR	NR	0.73	(0.51–1.04)
			3	NR	NR	0.84	(0.60–1.19)
			4	NR	NR	0.84	(0.60–1.18)
			5	NR	NR	0.91	(0.66–1.27)
			Total 135,894				p = 0.9‡
DHA
Parkinson's Disease	Chen, 200334	Men	Quintiles					Multivariable adjustors: Age, smoking (cigarettes/day), energy intake (quintiles), alcohol consumption
	Cohort Study: Health Professional Follow-up Study and The Nurses' Health Study		1	NR	0.02 % of energy	1
			2	NR	0.05 % of energy	0.79	(0.49–1.28)
			3	NR	0.07 % of energy	1.05	(0.67–1.64)
			4	NR	0.1 % of energy	0.90	(0.57–1.42)
			5	NR	0.2 % of energy	0.92	(0.58–1.44)
			Total 47,331				p = 0.9‡
		Women	Quintiles
			1	NR	0.02 % of energy	1
			2	NR	0.04 % of energy	0.62	(0.36–1.07)
			3	NR	0.06 % of energy	0.65	(0.38–1.09)
			4	NR	0.08 % of energy	0.81	(0.49–1.32)
			5	NR	0.1 % of energy	0.76	(0.46–1.26)
			Total 88,563				p = 0.8‡
		Pooled men and women	Quintiles
			1	NR	NR	1
			2	NR	NR	0.71	(0.49–1.02)
			3	NR	NR	0.86	(0.61–1.21)
			4	NR	NR	0.86	(0.61–1.20)
			5	NR	NR	0.84	(0.60–1.18)
			Total 135,894				p = 0.8‡

*

NR = Not Reported;

† Number of people included in analysis;

‡ test for trend.

|| Core variables = Age of child, sex, maternal age at menarche, maternal age at delivery, maternal chronic disease, previous spontaneous abortion, persistent vomiting during index pregnancy, multiple pregnancy, number of obstetric visits, timing of membrane rupture, use of general anesthesia, mode of delivery, abnormal placenta, head circumference, evident congenital malformation, place of deliver, use of iron during pregnancy, intentional physical exercise during pregnancy, painless delivery classes;

§ Risk of MS per 100 grams of fish per day (log transformation).

Overall effect. We identified four studies^{34, 43, 60, 61} that specifically addressed the association of omega-3 FA consumption with risk or incidence of particular neurological diseases other than dementia: two assessed the incidence of MS,^{43, 61} one assessed the risk of Parkinson's disease,³⁴ and one assessed the risk of cerebral palsy⁶⁰ (Table 3.6).

The relationship between dietary intake of omega-3 FA and incidence of MS was assessed in two reports; one pooled data from two large cohorts of women from the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II),⁶¹ and the other used a case-control design.⁴³ The prospective cohort study assessed the effect of omega-3 fatty acids in terms of fish consumption, fish omega-3 FA, ALA, EPA, and DHA (Table 3.6). ALA was associated with a reduced risk of MS in both cohorts that did not reach statistical significance (pooled RR = 0.3; 95% C.I. 0.1–1.1) (Table 3.6). Intakes of omega-3 FA, EPA, or DHA were not associated with MS incidence. Relative risk estimates pooled for both NHS and NHS II cohorts for omega-3 FA intake (fish) were 1.1 (95% C.I. 0.9–1.3), for EPA intake, 1.3 (95% 0.9–1.9), and 1.1 (95% C.I. 0.9–1.5) for DHA intake (Table 3.6). The case-control study⁴³ evaluated 197 incident MS cases and 202 age-, sex- and neighborhood-matched controls and found no significant association between fish consumption and risk of MS overall (OR = 0.91, 95% C.I. 0.78–1.05). However, fish consumption was significantly associated with a lower risk of MS in females only (OR = 0.83, 95% C.I. 0.69–1.00; p<0.05) (Table 3.6).

The relationship between dietary intake of omega-3 FA and incidence of Parkinson's disease was assessed in one report that pooled data from two large prospective cohorts, the Health Professionals Follow-up Study and the Nurses' Health Study. This study assessed the effect of omega-3 FA in terms of omega-3 fats from fish, ALA, EPA, and DHA over a six- to eight-year period (Table 3.6). There was no significant association between fish omega-3 FA, ALA, EPA, or DHA intake and risk of Parkinson's disease (p for trend = 0.9, 0.9, 0.9 and 0.8, respectively).

In a pooled analysis of men and women across two cohorts, ALA was associated with a reduced risk of developing Parkinson's disease (RR = 0.65, 95% CI 0.46, 0.91 for comparison of highest to lowest quintiles of risk). Among women, there was a significant trend but no significant risk reduction for any individual quintile of consumption. This finding is particularly noteworthy given the statistical power of the Health Professionals Follow-up Study and the Nurses' Health Study and the longitudinal analysis of dietary intake in these studies.

One study⁶⁰ evaluated the effects of maternal dietary intake on the risk of cerebral palsy in offspring in a case-control study of 91 cases of cerebral palsy identified from statistics of hospitals and rehabilitation centers in Greece and 246 neighborhood controls. Mothers of cases and controls were interviewed about their dietary habits during pregnancy using a food-frequency questionnaire. Consumption of fish once a week throughout pregnancy was associated with a lower risk of cerebral palsy (OR= 0.63, 95% C.I. 0.37–1.08; p < 0.09) compared with no fish intake.

Sub-populations. Two studies^{34, 43} stratified the effects of omega-3 FA by gender. The study that investigated the relationship between dietary intake of fat and Parkinson's disease found no apparent association between omega-3 FA intake and risk of Parkinson's disease for either males or females (p for trend = 0.9 for males and 0.8 for females).

In the other study,⁴³ which used a case-control design, fish consumption was associated with a reduced risk of MS among females, (OR = 0.83, 95% C.I. 0.69–1.00) but not males (OR = 1.08, 95% C.I. 0.84–1.40) (Table 3.6).

Covariates. Effects of any specific covariates on the observed omega-3 associations were not reported in any of the studies.

Effects of source, dose, and exposure duration

Source: The effect of fish consumption on the incidence of two different neurological diseases was assessed in three different reports. Fish consumption was associated with a reduced risk of cerebral palsy;⁶⁰ it had no overall effect on the incidence of MS in two studies,^{43, 61} but was associated with a reduced risk for women in one.⁴³ Omega-3 FA from fish had no effect on the incidence of MS⁴³ or Parkinson's disease.³⁴ ALA was associated with a reduced risk of MS in one study⁶¹ and had no effect on the incidence of Parkinson's disease in another.³⁴ EPA and DHA had no effect on the incidence of MS⁶¹ or Parkinson's disease.³⁴

Dose: Dose effect was assessed in two studies.^{34, 61} One study³⁴ assessed the effect of fish dose on the incidence of MS and found no dose (or other) effect. A dose effect for ALA on the incidence of MS was reported in one study,³⁴ but no dose effect for ALA on the incidence of Parkinson's disease was found in the other study.⁶¹ There was no dose effect for EPA or DHA in either study.

Exposure Duration: None of the studies assessed the effect of exposure duration.

Sustainment of effect. Sustainment of effect was not assessed in any of the reports.

Table 3.5 Parameters of methodological quality.*

Table 3.5 Parameters of methodological quality.*

Parameters	Chen, 200334	Ghadirian, 199843	Petridou, 199860	Zhang, 200061
Adjustment for confounders	Y	Y	Y	Y
Blinding of exposure/outcome	Y	Y	Y	Y
Valid ascertainment of outcome	Y	Y	Y	Y
Valid ascertainment of exposure	Y	Y	Y	Y
Exposure before outcome	Y	Y	Y	Y
Selection bias	N	N	Y	N
Description of withdrawals and dropouts	NR	Y	Y	Y

*

NR = not reported.

Quality and applicability. Parameters of methodologic quality are detailed in Table 3.5. All four of the studies^{34, 43, 60, 61} had an applicability rating of II.

Progression of Multiple Sclerosis

Table 3.7 The effect of omega-3 fatty acids on progression (more...)

Table 3.7 The effect of omega-3 fatty acids on progression of multiple sclerosis reported in one randomized controlled trial (RCT).*

Author, Year	Treatment Group	Disability, number (%)of patients						Mean relapse rates
Bates, 198940		Overall		Kurtzke ≤ 2		Duration ≤ 5 years		Kurtzke ≤ 2		Kurtzke > 2
		Better/same	Worse	Better/same	Worse	Better/same	Worse	Better/same	Worse	Better/same	Worse
	Max EPA 10 grams/day for 24 months	79 (51)	66 (43)	50 (59)	35 (41)	30 (57)	23 (43)	0.44	0.15	0.55	0.05
	Olive oil 10 grams/day for 24 months	65 (42)	82 (52)	41 (46)	49 (54)	24 (42)	33 (58)	0.55	0.16	0.63	0.70

*

No significant difference between groups for any comparisons.

Overall effect. We identified three studies that evaluated the effect of omega-3 FA on the treatment and progression of MS. Among these, one study was an RCT⁴⁰ and two were single arm, open-label clinical trials.^{62, 63} The RCT assessed the effect of treatment with an omega-3 FA supplement (MaxEPA) on disability and relapse rates (Table 3.7). There were no significant differences in disability or relapse rates between the treatment and placebo groups. Results for disability did not differ on subgroup analyses of patients with disease duration of 5 years or less and baseline Kurtzke disability scores of 2 or less (Table 3.7).

Table 3.8 The effect of omega-3 fatty acids on progression (more...)

Table 3.8 The effect of omega-3 fatty acids on progression of multiple sclerosis in open-label trials stratified by outcome

Author, Year	Intervention	Mean EDSS Scores*	Mean Progression Index
		n, clinical diagnosis	Before	After	Before	After
Cendrowski, 198662	MaxEPA (4.2 g/day EPA; 2.8 g/day DHA)	5, acute remitting MS	3.30	2.70	0.59	0.44†
Cendrowski, 198662	MaxEPA (4.2 g/day EPA; 2.8 g/day DHA)	7; slowly progressive MS	6.92	7.07	0.35	0.36
Nordvik, 200063	Fish oil supplement (0.4 g/day EPA; 05 g/day DHA)	16; MS	2.16	1.63‡	NA	NA

NA = Not Applicable;

*

EDSS = Expanded Disability Status Scale;

† p < 0.05;

‡ = p = 0.005.

The one-arm open-label studies^{62, 63} described the effects of supplementation with omega-3 FA on disability and progression among patients with MS (Table 3.8). Both studies reported a significant reduction on the Expanded Disability Status Scale (EDSS) after treatment with the omega-3 supplement; one also reported improvement on an index of disease progression.⁶²

Sub-populations. The effects of omega-3 FA on subpopulations were not assessed.

Covariates. The effects of covariates on omega-3 FA effects were not assessed.

Effects of source, dose, and exposure duration

Source: The source of omega-3 FA was fish oil in one study⁶³ and fish oil capsules in the other.⁶²

Dose: A single dose was assessed in each study; hence, dose effect was not assessed.

Exposure Duration: The effect of exposure duration was not assessed.

Sustainment of effect. Sustainment of effect was not assessed.

Table 3.9 Relationship between methodologic quality (more...)

Table 3.9 Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on progression of multiple sclerosis in randomized controlled trials (RCTs)

		Methodologic Quality
Applicability		A	B	C
	I
	II		Bates40
	III

Quality and applicability. The RCT⁴⁰ had an applicability rating of II-B and a summary quality score of B (Jadad score = 3); concealment of allocation was not reported. This study is applicable to the general population of adult patients with multiple sclerosis (Table 3.9). The two open label one-arm trials^{62, 63} were both of poor methodologic quality: there was no comparison group or blinding; additionally there was no description of withdrawals or dropouts. Both of these trials had a Jadad score of 0. The applicability rating of these studies was II-B.

Overview

We screened 5,868 titles, from which we reviewed 500 full-text articles. Among these, 62 articles met our inclusion criteria for further review. Fifty were rejected and 12 met our inclusion criteria and were reviewed further for data abstraction. Among these, two articles were randomized controlled trials, six articles were prospective cohort studies, two articles were case-controls, and two were one-arm open label trials.

Main Findings

Limitations

It is important to point out that a major limitation of studies of omega-3 FA and disease is the lack of standardized methods to measure nutrient intakes.⁶⁸ Thus, it is possible to overestimate or underestimate true associations with outcomes, because of errors in measurement of nutrients.

Furthermore, the studies we reviewed lacked a uniform or consistent approach to quantifying the type of omega-3 FA. For example, some measured nutrient intake from food frequency questionnaires without reporting type of fish or method of preparation; other studies defined omega-3 fatty acid supplements. This issue will increasingly become important in the design of future studies of omega-3 fatty acids and disease.

Another major limitation with respect to studies relating omega-3 FA interventions to dementia, particularly Alzheimer's disease, is that the majority of studies have been done in subjects aged 60 and older. Since the length of the latency period for AD is unknown and may precede the presentation of any symptoms by several decades, the potential effect of implementing dietary interventions aimed at prevention at an advanced age may be limited. Furthermore, in studies that assessed the effects of omega-3 fatty acids on cognitive function in normal aging or dementia, standard measures often are not used or the instruments used to assess cognitive function lack uniformity.

It is also important to note that in observational studies, it is not possible to control exposure,⁶⁹ which can lead to confounding.⁷⁰

An additional limitation is the possibility of publication bias. For large observational studies, this issue is slightly different than that observed for randomized trials. Publication bias for the latter generally means that no results of the trial are published at all. For the former, which are the main source of evidence for this report, findings may be published, but only for outcomes that achieve statistical significance, with no regard for whether such outcomes were secondary in nature. Results for primary outcomes may not be published. We must interpret our findings in light of such possible publication bias.

It is possible that additional information that would change our conclusions is available in reports that we were unable to locate or for which we were unable to find a translator. However, among 505 requested articles, only five were not found, and we were able to screen all 500 articles retrieved.

Conclusions

For each of the conditions assessed in this report, conclusions can be drawn from a few studies on the effects of Omega-3 FA. Additionally, the strength of evidence for effects of omega-3 FA on outcomes in the conditions assessed varies greatly. The evidence suggests a possible association between omega- 3 FA and reduced risk of dementia. However, due to the small number of studies that inform this topic, further research is necessary before a strong conclusion can be drawn. Data are insufficient to draw conclusions about the effects of omega-3 FA on incidence of Parkinson's disease, cerebral palsy, or MS. In addition, the evidence regarding the progression of MS is inconsistent and inconclusive. There was insufficient evidence in the studies that met our systematic inclusion criteria to draw any substantive conclusions on omega-3 fatty acid intake. The paucity of evidence in this area suggests that further epidemiological and clinical research remains to be done before any conclusions can be drawn or policy recommendations can be made in this area.

Future Research

We offer the following observations and recommendations regarding future research on the effects of omega-3 FA on the various neurological conditions reviewed.

1. Additional research on the effects of omega-3 FA needs to be performed on all of the conditions reviewed in this report before recommendations regarding the use of omega-3 FA can be made for these conditions.

2. Of particular importance, properly designed randomized clinical trials that are sufficiently powered and of an adequate length (e.g. three to five years of follow-up) need to be conducted for dementia, especially Alzheimer's disease, as distinct from vascular dementia.

3. Given the concern described above regarding the possible difficulty of conducting valid studies on dementia, due to a lengthy presymptomatic latency period, it would be of interest to conduct intervention clinical trials of omega-3 fatty acids in middle-aged adults as well as in populations of cognitively-impaired adults prior to a dementia diagnosis, such as individuals with various sub-types of mild cognitive impairment (MCI).

4. Properly designed randomized clinical trials that are sufficiently powered and of an adequate length (e.g. three to five years of follow-up) need to be conducted for multiple sclerosis.

5. Studies should address the effects of different types of omega-3 fatty acids (i.e. DHA, EPA, ALA, and total omega-3 FA) as well as the ratio of omega-3 to omega-6 FA.

6. Studies that assess the effects of omega-3 FA should be designed to evaluate the effect of source, dose, treatment duration, and the sustainment of effect after discontinuation of omega-3 FA consumption.

7. Trials of omega-3 FA should include a baseline assessment of dietary omega-3 and omega-6 FA intake.

8. In controlled trials that assess the effects of omega-3 FA, analysis should include and report explicit testing of the effects of the omega-3 FA relative to the control substance.

9. All studies that assess the effects of omega-3 FA should use standard validated instruments to assess clinical outcomes.

10. Studies that investigate the effects of omega-3 FA on cognition should include repeated measures of cognitive function using standard validated instruments to evaluate within-person cognitive change.

11. All studies that assess the effects of omega-3 FA should use standard validated dietary assessment instruments to assess nutritional intake.

12. Observational studies should report data about type of fish consumed and method of preparation.

13. Observational studies focused on repeated measures of diet for long-term intake, and sub-group analysis among persons with cardiovascular conditions (including history of stroke or myocardial infarction) also need to be performed in order to determine whether change in diet among these sub-groups results is confounding.

Preliminary Research Questions

Table A.1.1 Preliminary research questions

GENERAL QUESTIONS: Questions posed for all three participating EPCs, for years 1 and 2.

1. What is the evidence that variable clinical effects may reflect differences in:

• Serving size (fish vs. dietary supplement);

• Source (fish, food, plant) vs. dietary supplement (fish oil, plant oil);

• Specific type(s) of omega-3 fatty acids (docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and alpha-linolenic acid (ALA), fish, fish oil), or the ratio of omega-6/omega-3 fatty acids used;

• Manufacturer (different purity, presence of other potentially active agents)?

2. What is the evidence for adverse events, side effects, or counter-indications associated with omega-3 fatty acids (DHA, EPA, DPA, ALA, fish oil, fish)?

3. What is the evidence that omega-3 fatty acids are associated with adverse events in specific subpopulations such as diabetics?

4. What are the mean and median intakes of DHA, EPA, DPA, ALA, fish, fish oil, omega-6, omega-6/omega-3 ratio in the US population?

5. What is the evidence that omega-3 fatty acids influence overall energy balance?

6. What is the evidence that accurate interpretation of the results of clinical studies is dependent on knowing the absolute fatty acid content of the baseline data, the relative fatty acid content of the baseline diet, or the tissue ratios of fatty acids (omega-6/omega-3) during the investigative period?

DISEASE-SPECIFIC QUESTIONS: questions posed to the SCEPC for Year 2 of the project:

Neurology:

1. What is the evidence that omega-3 fatty acids play a role in maintaining cognitive function with aging?

2. What is the evidence that the level of brain or retinal DHA levels affect the incidence of neurological diseases?

Technical Expert Panel

Table A.2.2 Key TEP comments and recommendations

Neurology

1. What is the evidence that omega-3 fatty acids play a role in maintaining cognitive function with aging?

• This question pertains to 1) both maintenance and gains in cognitive functioning with normal aging, and 2) the prevention of dementia..

• The literature primarily includes studies on Alzheimers' disease, but other forms of dementia are also of interest.

• Normative data should be used to measure cognitive function.

• Focus on domains of cognitive function rather than specific tests. Domains of function include 1) general memory, 2) working memory, and 3) executive function.

• Part B of the Trail Making Test and praxis components of the ADAS-Cog are scales that can be used to define normal cognitive function.

• The following instruments can be used to screen for or assess cognitive function in dementia: the Folstein Mini Mental Status Exam, the Alzheimer's Disease Assessment Scale, the Modified Mini-Mental State Examination, and the Telephone Interview of Cognitive Status.

• Look at cognitive domains that are likely to change with aging: executive function, concentration, perceptual/motor processing, verbal learning and memory, verbal and spatial working memory and semantic memory.

• There is no single answer regarding the time frame within which an improvement or decline in cognitive function would occur. Most studies range from 6 months to 1–2 years. To determine the impact of a treatment, you would need to look at the impact over a period of years.

• To determine an effect over time, it may be necessary to look at large observational studies.

• There is more likely to be data on decline over time than on improvement.

• For mild cognitive impairment where there is a significant problem with memory only, look for a change in the conversion rate and at historical cohort studies.

• Look at whether omega-3 fatty acids are both preventing and staving the course of dementia.

• A new set of measurements was published two years ago to assess the rate of change. Do not restrict to these criteria, however, since all of the data should be examined.

• The minimum age limit to assess cognitive function with aging should be 50 years. Other neurological diseases have earlier onset so the age limit should be 45 years for those diseases.

2. What is the evidence that the level of brain or retinal DHA levels affect the incidence of neurological diseases?

• Do not restrict the review to studies that assess brain or retinal levels of DHA.

• Look at brain levels separate from blood levels

• This question is marginal compared to Question #1 and could be limited.

• The mechanisms that affect DHA levels are unknown.

• It would be helpful to have data on blood levels to show the link between dietary intake of omega-3 fatty acids and blood levels.

• If a study doesn't report blood levels, it should not be included.

• The accuracy of dietary intake data is not as effective as blood levels, but dietary intake studies should not be excluded.

• It is critical to include information on studies that have negative results.

• For studies that compare supplements versus placebo, it is important to get information on dose effect.

• The evidence available for dementia is disproportionate to other neurological diseases. Other diseases to consider include Attention Deficit Disorder and non-verbal learning disabilities.

• This question is not necessarily restricted to adults.

• Focus on the effects of omega-3 fatty acids on disease incidence rather than on the effects of omega-3 fatty acids on prevalent disease, except for multiple sclerosis. For multiple sclerosis, the effects of omega-3 fatty acids is of interest.

• Revise the key questions as follows:

ο What is the evidence that omega-3 fatty acids play a role in maintaining cognitive function in normal aging?

ο What is the evidence that omega-3 fatty acids affect the incidence of dementia including Alzheimer's disease?

ο What is the evidence that omega-3 fatty acids are effective in the treatment of dementia including Alzheimer's disease?

ο What is the evidence that omega-3 fatty acids affect the incidence of neurological diseases?

ο What is the evidence that omega-3 fatty acids prevent the progression of multiple sclerosis?

Industry Experts

Figure A.3.1 Letter sent to industry experts

Search Strategies

Inclusion/Exclusion Criteria

Evidence Grading System

Figure A.6.1 Jadad score of methodologic quality.*

External Peer Reviewers

B.1 Literature Screener Form

B.2 Quality Review Form