Casey Adams05.03.10
An epidemic is unfolding among the elderly. Dementia now affects 14% of all U.S. adults over age of 71, with more than 1.8 million severe cases. The Alzheimer’s Association’s 2010 report indicates that 5.3 million Americans now have Alzheimer’s disease (AD) and they are being cared for by almost 11 million unpaid caregivers. It’s also the seventh leading cause of death in the U.S.
An all-out war is being waged against dementia. Recently, the NIH’s National Institute on Aging partnered with the McKnight Brain Research Foundation. Together they will fund 17 research grants totaling $28 million to investigate possible interventions for cognitive decline and dementia. And nutraceuticals have an important role to play here.
In one study, researchers will examine whether dietary supplements of omega 3 fatty acids and blueberries can slow or prevent age-related cognitive decline in older adults. The study will assess changes in memory and daily functioning over one year to determine the impact of these non-pharmaceutical interventions.
Consumers are also concerned. According to a health and wellness survey conducted by the Natural Marketing Institute (NMI), Harleysville, PA, the percentage of Americans who purchased brain and memory supplements more than doubled from 2007 to 2009. In 2007, nearly 4% of those surveyed from the general population used brain and memory supplements. In 2008 that number reached more than 7%. In 2009 it jumped again to almost 9%.
Markers of Cognitive Decline
Dementia comes in several forms. Alzheimer’s, with its characteristic beta-amyloid deposits, is the leading type of dementia. Vascular dementia and Lewy body dementia follow in prevalence. Vascular dementia is characterized by the narrowing and congestion of blood vessels feeding brain tissues. Lewy body dementia is characterized by alpha-synuclein deposits within nerve tissues.
Synapse loss and the degeneration of brain tissues within the cortices and hippocampus are common among all forms of dementia. Progression toward dementia is symptomized by gradual cognitive decline. In its early stages, this is referred to as mild cognitive impairment or MCI.
Parris Kidd, PhD, a leading cognitive nutraceutical researcher, points out the complexity of dementia mechanisms: “Dementia is characterized by brain atrophy, beginning in the cortex. Neurons are diminished in number. Dendrites atrophy and synapse density declines. Oxidative damage is involved. Beta-amyloid and neurofibrillary tangles likely interact with circulatory insufficiency to worsen the damage.”
In a review paper published in Alternative Medicine Review(1), Dr. Kidd outlines another mechanism related to cognitive decline: Mitochondrial oxidative phosphorylation. This embraces Schipper’s Free Radical-Mitochondrial theory of aging. With the conversion of oxygen and glucose in the Krebs cycle comes cumulative damage to mitochondria—our cell’s energy centers—from radical oxygen species. With this damage comes a reduction in mitochondria efficiency and reduced brain function. “As radical oxygen species interact with other toxins, the oxidative burden upon the mitochondria within brain cells may accumulate over time,” Dr. Kidd explained.
Many cognition researchers agree that lipid oxidative damage is at the forefront of this burden. Nutraceutical researcher Frank Schonlau, PhD, director of scientific communication for Switzerland-based Horphag Research explains the role of oxidation among brain neurons: “There is a relationship between memory improvement and the decreased presence of oxidized nerve membrane lipids in the blood. Nerve cell membranes are very rich in polyunsaturated fatty acids, which are sensitive to free radicals.”
“Inflammaging, a chronic state of inflammation due to oxidative damage, influences memory, cognition and Alzheimer’s disease progression,” adds Lakshmi Prakash, PhD, vice president of innovation and business development, Sabinsa Corporation, East Windsor, NJ.
Increased oxidative damage goes hand in hand with the formation of the amyloid-beta plaque that characterizes Alzheimer’s. The conventional understanding has been that Abeta fibrils are the primary elements of neuron deficiency in AD. New evidence indicates that soluble Abeta oligomers circulating among neurons and cerebrospinal fluid are primary in synaptic reduction and neuron damage.
The progressive assembly of neurotoxic amyloid fibrils or plaques are formed through the enzyme acetylcholinesterase. By this time, however, much of the neuron damage may have already been done, orchestrated through the Abeta oligomers. This was illustrated in a 2010 ELISA study of amyloid-beta content among 25 elderly adults. The study found higher counts of Abeta oligomers circulating within the cerebrospinal fluid of those with AD or MCI(2).
These problems are compounded by circulatory deficiencies, including reduced nutrient supply to brain tissues due to narrowed arteries. Damage from oxidative LDL and other radical species are implicated in this scenario as well.
Antioxidant Phytonutrients
“Oxidative stress is a major factor in brain aging. This stress can be reduced by including dietary antioxidants in the daily diet. One of the best ways to do this is by eating a lot of colorful fruits and vegetables each day,” said Kasi Sundaresan, PhD, scientific and quality specialist from iTi Tropicals, Inc., Lawrenceville, NJ. “Most tropical fruits are rich sources of antioxidants. Fruits with a high concentration of antioxidants acai, mangosteen, guava, papaya, mango and others.”
Phenolic compounds in general have been found to reduce Abeta oligomers and Abeta aggregation among neurons. Abeta reduction has been shown specifically in vivo for herbal compounds, such as curcumin (found in tumeric), ferulic acid (found in oats, wheat, apples, artichokes, rice, peanuts, oranges and pineapples), myricetin (a flavonoid found in various fruits, vegetables, walnuts and some herbs), nordihydroguaiaretic acid (found in chaparral, Larrae tridentata) and rosmarinic acid (found in rosemary, oregano, sage and mints).
Diets heavy in fruits and vegetables in general appear to reduce dementia and cognitive decline risk. A 2009 study published in the Journal of the American Medical Association (JAMA) followed 1410 adults, 65 years of age or older, for five years. Those who ate a predominantly Mediterranean Diet had a significantly slower rate of cognitive decline(3). Another 2009 study followed 1393 New Yorkers. Again, the Mediterranean Diet proved to significantly reduce both MCI and the risk of Alzheimer’s(4). Furthermore, contrasting the genetic theory of dementia, a 2009 study followed 3779 Swedish twins for 30 years. Those twins with diets with more fruits and vegetables had a significantly reduced risk of dementia(5).
Concentrated green foods provide a convenient method of increasing phytonutrient intake, according to David Sandoval, author and president of Organic By Nature, Inc., Ventura, CA, a leading supplier of dehydrated and concentrated fruits and vegetables. “Young cereal grasses like wheat grass and barley grass contain an array of nutrients, as well as superoxide dismutase,” Mr. Sandoval said. And SOD in particular has been found to be lower in Alzheimer patients(6).
RFI Ingredients, Blauvelt, NY, supplies focused antioxidant ingredients for food fortification. These include Oxyphyte, a combination of phytonutrients derived from antioxidant-rich food extracts; and Chocamine, a patented cocoa-based ingredient that provides all of the benefits of chocolate without the fat, sugar and calories. “RFI recently completed a clinical trial involving 40 healthy adult volunteers to measure the impact of Chocamine supplementation on short-term memory and other cognitive markers. The results showed that Chocamine improves short-term memory and performance,” explained RFI Ingredients CEO Jeff Wuagneux.
Studies showing the antioxidant resveratrol’s cognitive and anti-aging benefits have captured media attention, perhaps due to its connection to a certain popular beverage. Nutraceutical forms of resveratrol have benefited from this attention.
Jiaherb, Inc. of Fairfield, N.J. extracts reservatrol from Polygonum cuspidatum, also known as giant knotweed. “We’ve experienced big growth in resveratrol sales since the end of 2008,” commented Jiaherb’s vice president Charlie Wang. “Most of our product is used in supplements, candies and now even in cosmetics.”
Pycnogenol, derived from Pinus pinaster or P. maritime—the French maritime pine tree—has also shown cognition benefits. In a collaborative study from Australia’s National Institute of Complementary Medicine, 101 elderly adults between 60 and 85 years of age took either 150 mg of Pycnogenol or a placebo for three months. Monthly assessments included attention, memory and psychomotor ability. The Pycnogenol group showed significant memory and cognitive improvements compared to controls(7).
“Oxidative injury to neuronal cell membranes impairs cognitive functions and this can be potently addressed by taking Pycnogenol,” said Horphag’s Dr. Schonlau—worldwide distributors of Pycnogenol.
Vitamins
Isolated vitamin supplementation has come under some criticism, but combination therapy is well supported. In a study of 141 MCI, AD and healthy elderly patients, blood tests indicated that dementia patients all had significantly reduced plasma levels of vitamins A and E, lutein, zeaxanthin, beta-cryptoxanthin, lycopene and alpha- and beta-carotene(8).
In fact, according to iTi Tropicals’ Dr. Sundaresan, “Some recent studies showed that the brain cells need vitamin C.” For example, University of Calgary researchers followed 894 volunteers over the age of 65 with no signs of dementia. After five years, those who took vitamin C and vitamin E and/or multivitamins during the five years had lower levels of cognitive decline and vascular cognitive impairment(9). Amla, acerola and camu camu are fruits with significant vitamin C content.
Tocotrienols and tocopherols—natural vitamin E contains four tocopherols and four tocotrienols—have long been hypothesized to increase cognitive abilities. Isolated alpha-tocopherol research has been disappointing, but mixed supplementation offers more potential. The Chicago Health and Aging Project from the Rush University Medical Center suggested this in a study of AD incidence among 1041 and 3718 adult subjects. Alzheimer’s incidence among users of mixed forms of vitamin E was lower than those among alpha-tocopherol users(10). “Alpha-tocotrienol crosses the blood-brain barrier and is bioavailable among brain tissues. Natural palm vitamin E contains a high concentration of this potent neuroprotective agent,” adds Daniel Yap Yee Leng, PhD, deputy head for Tocotrienol R&D for Davos Life Science Pte, Ltd., Singapore—producer of tocotrienol Natural e3.
Niacin is another cognition-friendly nutrient. In a study published in the Journal of Neurosurgical Psychiatry, 3718 volunteers were followed for five years. Those consuming 22.5 mg/day of niacin from food had an 80% lower risk of Alzheimer’s, while those taking niacin supplements (17-45 mg/day) had a 70% reduction in AD risk. Niacin’s reduced AD risk effect was more pronounced when multivitamins and antioxidants were included with niacin supplementation(11).
Herbal Extracts
The herb ginkgo biloba, had been universally accepted as a brain tonic until its research hit a snag. A highly publicized 2009 study (GEM=The Gingko Evaluation of Memory study), published in the JAMA, reported that among 2874 elderly adults from senior centers, 240 mg of a ginkgo extract taken daily for an average of six years did not delay dementia incidence compared to placebo(12).
This finding contrasted with other studies showing that ginkgo increased cognition. A Cochrane Library review of 36 ginkgo studies, which narrowed the field to a group of nine placebo-controlled studies among 2016 patients, revealed several strong results showing ginkgo’s ability to enhance cognition(13).
A 2009 study from Switzerland’s Münsterlinge Psychiatric Hospital adds another notch for ginkgo, while possibly revealing part of the reason for ginkgo’s inconsistent results. The researchers gave 59 elderly adults with mild cognitive impairment a 90 mg fresh plant extract of ginkgo for six weeks. After the six weeks, improvements in memory and concentration, along with reductions in forgetfulness occurred for more than half of the patients(14).
Draco Natural Products’ (San Jose, CA) Brien Quirk has other questions about the protocols of the GEM study. “The GEM study should have had a good result if the subjects had followed a better diet, instead of the diets typical of U.S. senior residence centers. I believe ginkgo may still offer a valuable benefit for those seeking to use it with a comprehensive healthy diet and lifestyle intervention to reduce the risk of cognitive decline,” said Mr. Quirk.
Periwinkle, also known as Vinca minor, has a long history of traditional cognition use. Vinpocetine is an alkaloid of the V. minor extract, vincamine. Vinpocetine passes easily through the blood-brain barrier to increase brain metabolism and blood flow. Vinpocetine has a stellar research record, with more than 150 studies showing cognition and memory improvements. Its mechanisms include inhibiting the phosphodiesterase-1 enzyme; inhibiting voltage-dependent sodium ion channels (protecting neurons from damage); interacting with glutamate receptors and preventing glutamate damage; protecting against hypoxia; increasing cerebral blood flow; and stimulating glucose metabolism(15). Vinpocetine is also reputed to increase serotonin levels.
“These mechanisms of action have been widely studied in humans and animal models. Of particular interest is the observed ability of vinpocetine to increase short-term memory and increase critical reaction time among healthy volunteers,” explained Cyvex Nutrition’s (Irvine, CA) president, Matt Phillips.
Several studies have shown turmeric’s (Curcuma longa) curcuminoids boost memory and delay AD progression. “University researchers found that components of Curcumin C3 Complex potentially help to correct defective clearance of beta-amyloid plaque in models of Alzheimer’s disease. Curcuminoids have bioprotectant effects against oxidative stress—including nitric oxide-based free radicals; its anti-inflammatory benefits at the molecular level; cytoprotective effects on neurons; immune support and blood circulation support benefits, all work together to support cognition and memory,” said Dr. Prakash of Sabinsa. Curcumin C3 Complex, Sabinsa’s patented form of isolated curcumin, has been used in more than 25 clinical studies.
Sage (Salvia officinalis) has been a traditional memory-enhancing herb used for centuries. In a randomized, placebo-controlled multi-center study from Tehran University’s Medical Sciences Department, 60 drops per day of sage were given to 42 elderly mild and moderate Alzheimer’s disease patients. After four months, cognitive functions improved significantly among the sage group(16).
Cat’s claw (Uncaria tomentosa), an herb from the Amazon rainforest, contains an oxindole alkaloid of particular interest to scientists looking for Alzheimer solutions. Researchers from the Medical University of Gdańsk found that the oxindole alkaloid mitraphylline extracted from cat’s claw significantly binded with the AD Abeta 1-40 protein(17).
Toyama Medical and Pharmaceutical University researchers found memory improvements during in vivo research from U. tomentosa’s total alkaloids(18).
Belleville, NJ-based Ecuadorian Rainforest, a leading global supplier of cat’s claw, reports strong and growing sales for cat’s claw. “I believe that there is great promise in cat’s claw for not only the treatment of cognitive disorders, but also for the prevention of many debilitating illnesses,” said Steve Siegel, vice president.
American ginseng, or Panax quinquefolius, has been used for centuries to boost memory and attention span. Ginseng is also adaptogenic. In a recent study from Australia’s Swinburn University with 32 healthy young adults, those taking Cereboost (a standardized extract of Panax quinquefolius produced by Naturex) had significant improvement of working memory and increased “calmness”(19).
“American ginseng has a unique ginsenoside profile and promising cognitive-enhancing properties linked to human cognition. This availability in Cereboost led us to evaluate its neurocognitive properties in humans for the first time,” says Alvin Ibarra, strategic research programs manager at Naturex.
Traditional Eastern Botanicals
Several traditional Ayurvedic and Chinese herbs are now receiving more attention for their effects on cognition and memory.
Bacopa monnieri, an ancient Ayurvedic remedy for memory and cognitive decline, has showed success in recent clinical studies. Oregon researchers reported a randomized, double-blind, placebo-controlled study of bacopa in the Journal of Alternative Complementary Medicine. Elderly participants were given 300 mg of bacopa extract or placebo for 12 weeks. Word recall memory and concentration were significantly improved among the bacopa group(20).
In addition, researchers from Australia’s University of Woolongong gave 76 middle-aged adults either bacopa or placebo. The bacopa group showed a significant increase in the recall of new information after three months(21).
Ayurvedic authority Shailinder Sodhi, ND, BAMS, and professor at Bastyr University explained some of bacopa’s mechanisms. “Bacopa is known to increase neurotransmitter activity. It has been traditionally used to enhance brain function and stimulate the regeneration of nerve and brain cells,” he said. Dr. Shailinder is also founder of Ayush Herbs, Redmond, WA.
Polygala tenuifolia is a traditional herb used for many centuries in Chinese medicine for cognitive difficulties. Researchers from Seoul National University and National Creative Research Initiative Center for Alzheimer’s Dementia and Neuroscience Research Institute gave the root extract of P. tenuifolia or placebo to 53 elderly adults. Constructive recall, memory, word list recognition and the Boston naming test scores were significantly improved among the P. tenuifolia extract group(22). “Polygala tenuifolia 10:1 extract ratio concentration is used for heart palpitations, amnesia and insomnia in Traditional Chinese Medicine,” said Draco’s Mr. Quirk.
The monoterpene glucosides from Paeonia lactoflora have been shown to provide antioxidant and antidepressant effects in several in vivo studies as well. This flowering herb—also called white peony—was named after the Trojan War Greek physician Paeon and is claimed to have healed the wounds of Pluto and other Greek gods.
Other Chinese herbs have shown cognitive success too. In a 1990 analysis, 80 adolescents with brain dysfunction were given a combination of Bupleurum chinense, Scutellaria baicalensis, Astragalus membranaceus, Codonopsis pilosula, Ligustrum lucidum and Lophatherum gracile. Among the treated group, 23 cases were “cured” and 46 cases were “improved.” The remaining 11 cases showed no effects. Interestingly, the 23 cured cases also experienced an increase of 10 units of IQ(23).
Phospholipids, Choline Donors and Fatty Acids
The science of cell metabolism has progressed rapidly during the past few years, and a number of nutraceuticals have proven to be efficacious for enhancing memory and improving cognition. Phospholipids are primary structural members for cell membranes. They are also critical to nerve cell electrical conduction. The three commercially available phospholipids are phosphatidylserine (PS), phosphatidylcholine (PC) and glycerophosphocholine (GPC). Of these, PS and GPC have shown the most promise for cognition in research.
“Phosphatidylserine is found most concentrated within the cells of brain tissue,” said Dr. Kidd. PS is central to mitochondrial energy production and synapse integrity. And synapse breakdown and energy failure are early features of Alzheimer’s disease, according to Dr. Kidd.
PS has been the subject of several cognitive studies over the past two decades, with significant results. In one multi-center, placebo-controlled Italian study, researchers gave 300 mg of PS per day for 6 months to 494 cognition-impaired elderly patients. The PS group showed significant improvements in behavior and cognition compared to the placebo group(24).
Stanford and Vanderbilt University researchers gave 149 age-associated memory-impaired patients 300 mg of PS or placebo per day for 12 weeks. The PS group improved in learning and memory performance assessments by 30% over the placebo group. Post-PS improvements were significantly greater among lower-performing adults(25).
CapsuleWorks’ PS product, Neuro-PS, is produced from natural soy lecithin. “Neuro-PS can help sharpen mental focus while helping to improve memory,” says Darren Schneider, vice president at CapsuleWorks.
Peter Rohde, CEO of Science & Ingredients, Inc., Laguna Niguel, CA, a leading supplier of PS and a proprietary PS-DHA combination, adds that “phosphatidylserine has so much well-documented research behind it, that it easily deserved FDA’s grant of two limited health claims.”
The FDA allows PS two health claims: “PS may reduce the risk of dementia in the elderly,” and “PS may reduce the risk of cognitive dysfunction in the elderly.”
Glycerophosphocholine research has also been impressive. “Research on GPC illustrates it has the ability to sharpen mental performance and concentration during middle age,” says Dr. Kidd. Several have shown GPC’s ability to increase focus, attention and reaction time, as well as reduce dementia risk. In one multi-center study, 2044 patients that had suffered cognitive damage from a recent stroke were given 1000-1200 mg per day of GPC for six months. Improvements in memory and reduced cognitive decline were higher among GPC patients(26).
“GPC has a mass of clinical and basic science data to support it. GPC is uniquely protective and has benefits for stroke and other brain damage that are potentially lifesaving and deserve further research.”
Citicoline (cytidine diphosphate choline, or CDP-choline) is another promising cognitive nutraceutical. “Citicoline is a source of choline, a building block of the neurotransmitter acetylcholine and more importantly cytidine. Cytidine is a pyrimidine with many positive and distinct effects compared to other brain nutrients,” said Karen Todd, RD, of Kyowa Hakko USA, New York, NY. Ms. Todd went on to explain that brain imaging technology has shown that Cognizin increases brain activity, and provides structural components for synthesizing brain cell membranes. “Cognizin also helps increase critical neurotransmitters such as dopamine and acetylcholine. It enhances cellular integrity by increasing phospholipid synthesis. It also supports cellular activity by increasing levels of adenosine triphosphate (ATP),” Ms. Todd added.
DHA is the primary omega 3 fatty acid found among brain cells. DHA appears to be most applicable to cognition as part of an integrated approach. In a study of 485 elderly adults, six months of 900 mg per day of DHA resulted in increased memory scores compared to placebo(27).
Further, the need for DHA during the developmental years is clear. A 2009 study of 229 infants showed that those who had received formula supplemented with DHA had increased cognitive development compared to infants fed regular infant formula(28).
The leading producer of infant-formula DHA is Martek Biosciences, Inc., Columbia, MD. Its DHA oil used in infant formula is produced from the algal species Crypthecodinium cohnii.
Another newer source of DHA is krill oil. Leading krill producer Aker BioMarine, out of Norway, recently signed an exclusive supply agreement with leading U.S. supplement brand Schiff Nutrition, Salt Lake City, UT.
Other Antioxidants
Acetyl L-carnitine (ALC) has a vital role in maintaining brain function as we age. ALC, the acetyl derivative of L-carnitine, is found throughout the central nervous system. “ALC plays a broad role in central nervous system metabolism as a source of acetyl groups for the synthesis of acetylcholine—a neurotransmitter vital to proper brain function and energy-production,” said Kevin Owen, PhD, head of scientific affairs, Lonza, Inc., Allendale, NJ.
The research confirms these effects. In a randomized, placebo-controlled study of 66 Italian centenarians, 2 grams of L-carnitine daily improved cognition and reduced fatigue after six months(29). Other research has showed ALC’s ability to reverse lipid peroxidation.
Research has shown promising results indicating CoQ10 may reduce the risk of cognitive decline. Dr. Kidd’s paper connecting mitochondrial insufficiency with cognitive disorders reviewed a study reporting improvement among 27 Alzheimer’s patients treated with CoQ10 in combination with other nutrients.
Two leading CoQ10 producers are China-based Zhejiang Medicine Company (ZMC) and Japan-based Kaneka Corporation. ZMC produces ubiquinone through a proprietary bacteria process, while ubiquinol is manufactured by Kaneka using yeast fermentation.
Research connecting alpha-lipoic acid with cognition improvement is well established. A 2007 study of 43 mild or moderate dementia patients showed that 600 mg of alpha-lipoic acid significantly reduced the rate of cognitive decline(30). Alpha-lipoic acid has also been shown to improve peripheral neuropathy and cardiac autonomic neuropathy(31). A recent review from the Institute for Brain Aging and Dementia concluded that alpha-lipoic acid is productive as part of an integrative program including other mitochondrial nutrients, such as L-carnitine and CoQ10(32).
R-alpha lipoic acid (RLA) and S-alpha lipoic acid (SLA) are the two enantiomers of ALA. Leading lipoic acid producer GeroNova Research, Inc. manufactures an ionic-stabilized (salt) form of RLA called Bio-Enhanced R-Lipoic Acid with improved stability, solubility and bioavailability. Preliminary pharmacokinetic trials by GeroNova found that the ionic-form of RLA reached blood concentrations of lipoic acid up to 40 times higher than those achieved with unstabilized RLA. “The R-form of alpha-lipoic acid is the form found in nature. Supra-physiological supplemented levels of RLA activate phase II detoxification enzymes,” says David Carlson, co-founder and director of R&D at GeroNova. “It was previously assumed that alpha-lipoic acid was a radical scavenger. However, it is now known that RLA upregulates cytoprotective genes among brain cells, making them more resistant to radical damage and reduces neuroinflammation. All of this activity is found in the R-enantiomer.”
The Integrated Nutraceutical Strategy
An integrated approach appears to be the most productive when it comes to reducing cognitive decline. This became apparent in a recent study of 35 elderly patients with mild dementia and depression from New York’s Stress Relief and Memory Training Center. Participants that underwent an integrative therapy incorporating multivitamins, vitamin E, lipoic acid, omega 3 and CoQ10 had significantly improved cognition, memory function and frontal lobe brain activity(33).
Just think (no pun intended) of what the dementia rates might look like with a fully integrated nutraceutical intervention approach. The incorporation of these nutrients along with a diet rich in fruits and vegetables, cognition-enhancing herbal extracts and the other potent nutraceuticals mentioned here now sits upon a strong scientific foundation.
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About the Author: Casey Adams, PhD, has more than two decades of natural foods and nutraceuticals industry experience, and a clinical practice in Watsonville, CA. He is also president of the consulting firm Realnatural, Inc., and the author of several books on natural health. His last article in Nutraceuticals World focused on the heart health market (November, 2009). He can be reached at ca@caseadams.com.
An all-out war is being waged against dementia. Recently, the NIH’s National Institute on Aging partnered with the McKnight Brain Research Foundation. Together they will fund 17 research grants totaling $28 million to investigate possible interventions for cognitive decline and dementia. And nutraceuticals have an important role to play here.
In one study, researchers will examine whether dietary supplements of omega 3 fatty acids and blueberries can slow or prevent age-related cognitive decline in older adults. The study will assess changes in memory and daily functioning over one year to determine the impact of these non-pharmaceutical interventions.
Consumers are also concerned. According to a health and wellness survey conducted by the Natural Marketing Institute (NMI), Harleysville, PA, the percentage of Americans who purchased brain and memory supplements more than doubled from 2007 to 2009. In 2007, nearly 4% of those surveyed from the general population used brain and memory supplements. In 2008 that number reached more than 7%. In 2009 it jumped again to almost 9%.
Markers of Cognitive Decline
Dementia comes in several forms. Alzheimer’s, with its characteristic beta-amyloid deposits, is the leading type of dementia. Vascular dementia and Lewy body dementia follow in prevalence. Vascular dementia is characterized by the narrowing and congestion of blood vessels feeding brain tissues. Lewy body dementia is characterized by alpha-synuclein deposits within nerve tissues.
Synapse loss and the degeneration of brain tissues within the cortices and hippocampus are common among all forms of dementia. Progression toward dementia is symptomized by gradual cognitive decline. In its early stages, this is referred to as mild cognitive impairment or MCI.
Parris Kidd, PhD, a leading cognitive nutraceutical researcher, points out the complexity of dementia mechanisms: “Dementia is characterized by brain atrophy, beginning in the cortex. Neurons are diminished in number. Dendrites atrophy and synapse density declines. Oxidative damage is involved. Beta-amyloid and neurofibrillary tangles likely interact with circulatory insufficiency to worsen the damage.”
In a review paper published in Alternative Medicine Review(1), Dr. Kidd outlines another mechanism related to cognitive decline: Mitochondrial oxidative phosphorylation. This embraces Schipper’s Free Radical-Mitochondrial theory of aging. With the conversion of oxygen and glucose in the Krebs cycle comes cumulative damage to mitochondria—our cell’s energy centers—from radical oxygen species. With this damage comes a reduction in mitochondria efficiency and reduced brain function. “As radical oxygen species interact with other toxins, the oxidative burden upon the mitochondria within brain cells may accumulate over time,” Dr. Kidd explained.
Many cognition researchers agree that lipid oxidative damage is at the forefront of this burden. Nutraceutical researcher Frank Schonlau, PhD, director of scientific communication for Switzerland-based Horphag Research explains the role of oxidation among brain neurons: “There is a relationship between memory improvement and the decreased presence of oxidized nerve membrane lipids in the blood. Nerve cell membranes are very rich in polyunsaturated fatty acids, which are sensitive to free radicals.”
“Inflammaging, a chronic state of inflammation due to oxidative damage, influences memory, cognition and Alzheimer’s disease progression,” adds Lakshmi Prakash, PhD, vice president of innovation and business development, Sabinsa Corporation, East Windsor, NJ.
Increased oxidative damage goes hand in hand with the formation of the amyloid-beta plaque that characterizes Alzheimer’s. The conventional understanding has been that Abeta fibrils are the primary elements of neuron deficiency in AD. New evidence indicates that soluble Abeta oligomers circulating among neurons and cerebrospinal fluid are primary in synaptic reduction and neuron damage.
The progressive assembly of neurotoxic amyloid fibrils or plaques are formed through the enzyme acetylcholinesterase. By this time, however, much of the neuron damage may have already been done, orchestrated through the Abeta oligomers. This was illustrated in a 2010 ELISA study of amyloid-beta content among 25 elderly adults. The study found higher counts of Abeta oligomers circulating within the cerebrospinal fluid of those with AD or MCI(2).
These problems are compounded by circulatory deficiencies, including reduced nutrient supply to brain tissues due to narrowed arteries. Damage from oxidative LDL and other radical species are implicated in this scenario as well.
Antioxidant Phytonutrients
“Oxidative stress is a major factor in brain aging. This stress can be reduced by including dietary antioxidants in the daily diet. One of the best ways to do this is by eating a lot of colorful fruits and vegetables each day,” said Kasi Sundaresan, PhD, scientific and quality specialist from iTi Tropicals, Inc., Lawrenceville, NJ. “Most tropical fruits are rich sources of antioxidants. Fruits with a high concentration of antioxidants acai, mangosteen, guava, papaya, mango and others.”
Phenolic compounds in general have been found to reduce Abeta oligomers and Abeta aggregation among neurons. Abeta reduction has been shown specifically in vivo for herbal compounds, such as curcumin (found in tumeric), ferulic acid (found in oats, wheat, apples, artichokes, rice, peanuts, oranges and pineapples), myricetin (a flavonoid found in various fruits, vegetables, walnuts and some herbs), nordihydroguaiaretic acid (found in chaparral, Larrae tridentata) and rosmarinic acid (found in rosemary, oregano, sage and mints).
Diets heavy in fruits and vegetables in general appear to reduce dementia and cognitive decline risk. A 2009 study published in the Journal of the American Medical Association (JAMA) followed 1410 adults, 65 years of age or older, for five years. Those who ate a predominantly Mediterranean Diet had a significantly slower rate of cognitive decline(3). Another 2009 study followed 1393 New Yorkers. Again, the Mediterranean Diet proved to significantly reduce both MCI and the risk of Alzheimer’s(4). Furthermore, contrasting the genetic theory of dementia, a 2009 study followed 3779 Swedish twins for 30 years. Those twins with diets with more fruits and vegetables had a significantly reduced risk of dementia(5).
Concentrated green foods provide a convenient method of increasing phytonutrient intake, according to David Sandoval, author and president of Organic By Nature, Inc., Ventura, CA, a leading supplier of dehydrated and concentrated fruits and vegetables. “Young cereal grasses like wheat grass and barley grass contain an array of nutrients, as well as superoxide dismutase,” Mr. Sandoval said. And SOD in particular has been found to be lower in Alzheimer patients(6).
RFI Ingredients, Blauvelt, NY, supplies focused antioxidant ingredients for food fortification. These include Oxyphyte, a combination of phytonutrients derived from antioxidant-rich food extracts; and Chocamine, a patented cocoa-based ingredient that provides all of the benefits of chocolate without the fat, sugar and calories. “RFI recently completed a clinical trial involving 40 healthy adult volunteers to measure the impact of Chocamine supplementation on short-term memory and other cognitive markers. The results showed that Chocamine improves short-term memory and performance,” explained RFI Ingredients CEO Jeff Wuagneux.
Studies showing the antioxidant resveratrol’s cognitive and anti-aging benefits have captured media attention, perhaps due to its connection to a certain popular beverage. Nutraceutical forms of resveratrol have benefited from this attention.
Jiaherb, Inc. of Fairfield, N.J. extracts reservatrol from Polygonum cuspidatum, also known as giant knotweed. “We’ve experienced big growth in resveratrol sales since the end of 2008,” commented Jiaherb’s vice president Charlie Wang. “Most of our product is used in supplements, candies and now even in cosmetics.”
Pycnogenol, derived from Pinus pinaster or P. maritime—the French maritime pine tree—has also shown cognition benefits. In a collaborative study from Australia’s National Institute of Complementary Medicine, 101 elderly adults between 60 and 85 years of age took either 150 mg of Pycnogenol or a placebo for three months. Monthly assessments included attention, memory and psychomotor ability. The Pycnogenol group showed significant memory and cognitive improvements compared to controls(7).
“Oxidative injury to neuronal cell membranes impairs cognitive functions and this can be potently addressed by taking Pycnogenol,” said Horphag’s Dr. Schonlau—worldwide distributors of Pycnogenol.
Vitamins
Isolated vitamin supplementation has come under some criticism, but combination therapy is well supported. In a study of 141 MCI, AD and healthy elderly patients, blood tests indicated that dementia patients all had significantly reduced plasma levels of vitamins A and E, lutein, zeaxanthin, beta-cryptoxanthin, lycopene and alpha- and beta-carotene(8).
In fact, according to iTi Tropicals’ Dr. Sundaresan, “Some recent studies showed that the brain cells need vitamin C.” For example, University of Calgary researchers followed 894 volunteers over the age of 65 with no signs of dementia. After five years, those who took vitamin C and vitamin E and/or multivitamins during the five years had lower levels of cognitive decline and vascular cognitive impairment(9). Amla, acerola and camu camu are fruits with significant vitamin C content.
Tocotrienols and tocopherols—natural vitamin E contains four tocopherols and four tocotrienols—have long been hypothesized to increase cognitive abilities. Isolated alpha-tocopherol research has been disappointing, but mixed supplementation offers more potential. The Chicago Health and Aging Project from the Rush University Medical Center suggested this in a study of AD incidence among 1041 and 3718 adult subjects. Alzheimer’s incidence among users of mixed forms of vitamin E was lower than those among alpha-tocopherol users(10). “Alpha-tocotrienol crosses the blood-brain barrier and is bioavailable among brain tissues. Natural palm vitamin E contains a high concentration of this potent neuroprotective agent,” adds Daniel Yap Yee Leng, PhD, deputy head for Tocotrienol R&D for Davos Life Science Pte, Ltd., Singapore—producer of tocotrienol Natural e3.
Niacin is another cognition-friendly nutrient. In a study published in the Journal of Neurosurgical Psychiatry, 3718 volunteers were followed for five years. Those consuming 22.5 mg/day of niacin from food had an 80% lower risk of Alzheimer’s, while those taking niacin supplements (17-45 mg/day) had a 70% reduction in AD risk. Niacin’s reduced AD risk effect was more pronounced when multivitamins and antioxidants were included with niacin supplementation(11).
Herbal Extracts
The herb ginkgo biloba, had been universally accepted as a brain tonic until its research hit a snag. A highly publicized 2009 study (GEM=The Gingko Evaluation of Memory study), published in the JAMA, reported that among 2874 elderly adults from senior centers, 240 mg of a ginkgo extract taken daily for an average of six years did not delay dementia incidence compared to placebo(12).
This finding contrasted with other studies showing that ginkgo increased cognition. A Cochrane Library review of 36 ginkgo studies, which narrowed the field to a group of nine placebo-controlled studies among 2016 patients, revealed several strong results showing ginkgo’s ability to enhance cognition(13).
A 2009 study from Switzerland’s Münsterlinge Psychiatric Hospital adds another notch for ginkgo, while possibly revealing part of the reason for ginkgo’s inconsistent results. The researchers gave 59 elderly adults with mild cognitive impairment a 90 mg fresh plant extract of ginkgo for six weeks. After the six weeks, improvements in memory and concentration, along with reductions in forgetfulness occurred for more than half of the patients(14).
Draco Natural Products’ (San Jose, CA) Brien Quirk has other questions about the protocols of the GEM study. “The GEM study should have had a good result if the subjects had followed a better diet, instead of the diets typical of U.S. senior residence centers. I believe ginkgo may still offer a valuable benefit for those seeking to use it with a comprehensive healthy diet and lifestyle intervention to reduce the risk of cognitive decline,” said Mr. Quirk.
Periwinkle, also known as Vinca minor, has a long history of traditional cognition use. Vinpocetine is an alkaloid of the V. minor extract, vincamine. Vinpocetine passes easily through the blood-brain barrier to increase brain metabolism and blood flow. Vinpocetine has a stellar research record, with more than 150 studies showing cognition and memory improvements. Its mechanisms include inhibiting the phosphodiesterase-1 enzyme; inhibiting voltage-dependent sodium ion channels (protecting neurons from damage); interacting with glutamate receptors and preventing glutamate damage; protecting against hypoxia; increasing cerebral blood flow; and stimulating glucose metabolism(15). Vinpocetine is also reputed to increase serotonin levels.
“These mechanisms of action have been widely studied in humans and animal models. Of particular interest is the observed ability of vinpocetine to increase short-term memory and increase critical reaction time among healthy volunteers,” explained Cyvex Nutrition’s (Irvine, CA) president, Matt Phillips.
Several studies have shown turmeric’s (Curcuma longa) curcuminoids boost memory and delay AD progression. “University researchers found that components of Curcumin C3 Complex potentially help to correct defective clearance of beta-amyloid plaque in models of Alzheimer’s disease. Curcuminoids have bioprotectant effects against oxidative stress—including nitric oxide-based free radicals; its anti-inflammatory benefits at the molecular level; cytoprotective effects on neurons; immune support and blood circulation support benefits, all work together to support cognition and memory,” said Dr. Prakash of Sabinsa. Curcumin C3 Complex, Sabinsa’s patented form of isolated curcumin, has been used in more than 25 clinical studies.
Sage (Salvia officinalis) has been a traditional memory-enhancing herb used for centuries. In a randomized, placebo-controlled multi-center study from Tehran University’s Medical Sciences Department, 60 drops per day of sage were given to 42 elderly mild and moderate Alzheimer’s disease patients. After four months, cognitive functions improved significantly among the sage group(16).
Cat’s claw (Uncaria tomentosa), an herb from the Amazon rainforest, contains an oxindole alkaloid of particular interest to scientists looking for Alzheimer solutions. Researchers from the Medical University of Gdańsk found that the oxindole alkaloid mitraphylline extracted from cat’s claw significantly binded with the AD Abeta 1-40 protein(17).
Toyama Medical and Pharmaceutical University researchers found memory improvements during in vivo research from U. tomentosa’s total alkaloids(18).
Belleville, NJ-based Ecuadorian Rainforest, a leading global supplier of cat’s claw, reports strong and growing sales for cat’s claw. “I believe that there is great promise in cat’s claw for not only the treatment of cognitive disorders, but also for the prevention of many debilitating illnesses,” said Steve Siegel, vice president.
American ginseng, or Panax quinquefolius, has been used for centuries to boost memory and attention span. Ginseng is also adaptogenic. In a recent study from Australia’s Swinburn University with 32 healthy young adults, those taking Cereboost (a standardized extract of Panax quinquefolius produced by Naturex) had significant improvement of working memory and increased “calmness”(19).
“American ginseng has a unique ginsenoside profile and promising cognitive-enhancing properties linked to human cognition. This availability in Cereboost led us to evaluate its neurocognitive properties in humans for the first time,” says Alvin Ibarra, strategic research programs manager at Naturex.
Traditional Eastern Botanicals
Several traditional Ayurvedic and Chinese herbs are now receiving more attention for their effects on cognition and memory.
Bacopa monnieri, an ancient Ayurvedic remedy for memory and cognitive decline, has showed success in recent clinical studies. Oregon researchers reported a randomized, double-blind, placebo-controlled study of bacopa in the Journal of Alternative Complementary Medicine. Elderly participants were given 300 mg of bacopa extract or placebo for 12 weeks. Word recall memory and concentration were significantly improved among the bacopa group(20).
In addition, researchers from Australia’s University of Woolongong gave 76 middle-aged adults either bacopa or placebo. The bacopa group showed a significant increase in the recall of new information after three months(21).
Ayurvedic authority Shailinder Sodhi, ND, BAMS, and professor at Bastyr University explained some of bacopa’s mechanisms. “Bacopa is known to increase neurotransmitter activity. It has been traditionally used to enhance brain function and stimulate the regeneration of nerve and brain cells,” he said. Dr. Shailinder is also founder of Ayush Herbs, Redmond, WA.
Polygala tenuifolia is a traditional herb used for many centuries in Chinese medicine for cognitive difficulties. Researchers from Seoul National University and National Creative Research Initiative Center for Alzheimer’s Dementia and Neuroscience Research Institute gave the root extract of P. tenuifolia or placebo to 53 elderly adults. Constructive recall, memory, word list recognition and the Boston naming test scores were significantly improved among the P. tenuifolia extract group(22). “Polygala tenuifolia 10:1 extract ratio concentration is used for heart palpitations, amnesia and insomnia in Traditional Chinese Medicine,” said Draco’s Mr. Quirk.
The monoterpene glucosides from Paeonia lactoflora have been shown to provide antioxidant and antidepressant effects in several in vivo studies as well. This flowering herb—also called white peony—was named after the Trojan War Greek physician Paeon and is claimed to have healed the wounds of Pluto and other Greek gods.
Other Chinese herbs have shown cognitive success too. In a 1990 analysis, 80 adolescents with brain dysfunction were given a combination of Bupleurum chinense, Scutellaria baicalensis, Astragalus membranaceus, Codonopsis pilosula, Ligustrum lucidum and Lophatherum gracile. Among the treated group, 23 cases were “cured” and 46 cases were “improved.” The remaining 11 cases showed no effects. Interestingly, the 23 cured cases also experienced an increase of 10 units of IQ(23).
Phospholipids, Choline Donors and Fatty Acids
The science of cell metabolism has progressed rapidly during the past few years, and a number of nutraceuticals have proven to be efficacious for enhancing memory and improving cognition. Phospholipids are primary structural members for cell membranes. They are also critical to nerve cell electrical conduction. The three commercially available phospholipids are phosphatidylserine (PS), phosphatidylcholine (PC) and glycerophosphocholine (GPC). Of these, PS and GPC have shown the most promise for cognition in research.
“Phosphatidylserine is found most concentrated within the cells of brain tissue,” said Dr. Kidd. PS is central to mitochondrial energy production and synapse integrity. And synapse breakdown and energy failure are early features of Alzheimer’s disease, according to Dr. Kidd.
PS has been the subject of several cognitive studies over the past two decades, with significant results. In one multi-center, placebo-controlled Italian study, researchers gave 300 mg of PS per day for 6 months to 494 cognition-impaired elderly patients. The PS group showed significant improvements in behavior and cognition compared to the placebo group(24).
Stanford and Vanderbilt University researchers gave 149 age-associated memory-impaired patients 300 mg of PS or placebo per day for 12 weeks. The PS group improved in learning and memory performance assessments by 30% over the placebo group. Post-PS improvements were significantly greater among lower-performing adults(25).
CapsuleWorks’ PS product, Neuro-PS, is produced from natural soy lecithin. “Neuro-PS can help sharpen mental focus while helping to improve memory,” says Darren Schneider, vice president at CapsuleWorks.
Peter Rohde, CEO of Science & Ingredients, Inc., Laguna Niguel, CA, a leading supplier of PS and a proprietary PS-DHA combination, adds that “phosphatidylserine has so much well-documented research behind it, that it easily deserved FDA’s grant of two limited health claims.”
The FDA allows PS two health claims: “PS may reduce the risk of dementia in the elderly,” and “PS may reduce the risk of cognitive dysfunction in the elderly.”
Glycerophosphocholine research has also been impressive. “Research on GPC illustrates it has the ability to sharpen mental performance and concentration during middle age,” says Dr. Kidd. Several have shown GPC’s ability to increase focus, attention and reaction time, as well as reduce dementia risk. In one multi-center study, 2044 patients that had suffered cognitive damage from a recent stroke were given 1000-1200 mg per day of GPC for six months. Improvements in memory and reduced cognitive decline were higher among GPC patients(26).
“GPC has a mass of clinical and basic science data to support it. GPC is uniquely protective and has benefits for stroke and other brain damage that are potentially lifesaving and deserve further research.”
Citicoline (cytidine diphosphate choline, or CDP-choline) is another promising cognitive nutraceutical. “Citicoline is a source of choline, a building block of the neurotransmitter acetylcholine and more importantly cytidine. Cytidine is a pyrimidine with many positive and distinct effects compared to other brain nutrients,” said Karen Todd, RD, of Kyowa Hakko USA, New York, NY. Ms. Todd went on to explain that brain imaging technology has shown that Cognizin increases brain activity, and provides structural components for synthesizing brain cell membranes. “Cognizin also helps increase critical neurotransmitters such as dopamine and acetylcholine. It enhances cellular integrity by increasing phospholipid synthesis. It also supports cellular activity by increasing levels of adenosine triphosphate (ATP),” Ms. Todd added.
DHA is the primary omega 3 fatty acid found among brain cells. DHA appears to be most applicable to cognition as part of an integrated approach. In a study of 485 elderly adults, six months of 900 mg per day of DHA resulted in increased memory scores compared to placebo(27).
Further, the need for DHA during the developmental years is clear. A 2009 study of 229 infants showed that those who had received formula supplemented with DHA had increased cognitive development compared to infants fed regular infant formula(28).
The leading producer of infant-formula DHA is Martek Biosciences, Inc., Columbia, MD. Its DHA oil used in infant formula is produced from the algal species Crypthecodinium cohnii.
Another newer source of DHA is krill oil. Leading krill producer Aker BioMarine, out of Norway, recently signed an exclusive supply agreement with leading U.S. supplement brand Schiff Nutrition, Salt Lake City, UT.
Other Antioxidants
Acetyl L-carnitine (ALC) has a vital role in maintaining brain function as we age. ALC, the acetyl derivative of L-carnitine, is found throughout the central nervous system. “ALC plays a broad role in central nervous system metabolism as a source of acetyl groups for the synthesis of acetylcholine—a neurotransmitter vital to proper brain function and energy-production,” said Kevin Owen, PhD, head of scientific affairs, Lonza, Inc., Allendale, NJ.
The research confirms these effects. In a randomized, placebo-controlled study of 66 Italian centenarians, 2 grams of L-carnitine daily improved cognition and reduced fatigue after six months(29). Other research has showed ALC’s ability to reverse lipid peroxidation.
Research has shown promising results indicating CoQ10 may reduce the risk of cognitive decline. Dr. Kidd’s paper connecting mitochondrial insufficiency with cognitive disorders reviewed a study reporting improvement among 27 Alzheimer’s patients treated with CoQ10 in combination with other nutrients.
Two leading CoQ10 producers are China-based Zhejiang Medicine Company (ZMC) and Japan-based Kaneka Corporation. ZMC produces ubiquinone through a proprietary bacteria process, while ubiquinol is manufactured by Kaneka using yeast fermentation.
Research connecting alpha-lipoic acid with cognition improvement is well established. A 2007 study of 43 mild or moderate dementia patients showed that 600 mg of alpha-lipoic acid significantly reduced the rate of cognitive decline(30). Alpha-lipoic acid has also been shown to improve peripheral neuropathy and cardiac autonomic neuropathy(31). A recent review from the Institute for Brain Aging and Dementia concluded that alpha-lipoic acid is productive as part of an integrative program including other mitochondrial nutrients, such as L-carnitine and CoQ10(32).
R-alpha lipoic acid (RLA) and S-alpha lipoic acid (SLA) are the two enantiomers of ALA. Leading lipoic acid producer GeroNova Research, Inc. manufactures an ionic-stabilized (salt) form of RLA called Bio-Enhanced R-Lipoic Acid with improved stability, solubility and bioavailability. Preliminary pharmacokinetic trials by GeroNova found that the ionic-form of RLA reached blood concentrations of lipoic acid up to 40 times higher than those achieved with unstabilized RLA. “The R-form of alpha-lipoic acid is the form found in nature. Supra-physiological supplemented levels of RLA activate phase II detoxification enzymes,” says David Carlson, co-founder and director of R&D at GeroNova. “It was previously assumed that alpha-lipoic acid was a radical scavenger. However, it is now known that RLA upregulates cytoprotective genes among brain cells, making them more resistant to radical damage and reduces neuroinflammation. All of this activity is found in the R-enantiomer.”
The Integrated Nutraceutical Strategy
An integrated approach appears to be the most productive when it comes to reducing cognitive decline. This became apparent in a recent study of 35 elderly patients with mild dementia and depression from New York’s Stress Relief and Memory Training Center. Participants that underwent an integrative therapy incorporating multivitamins, vitamin E, lipoic acid, omega 3 and CoQ10 had significantly improved cognition, memory function and frontal lobe brain activity(33).
Just think (no pun intended) of what the dementia rates might look like with a fully integrated nutraceutical intervention approach. The incorporation of these nutrients along with a diet rich in fruits and vegetables, cognition-enhancing herbal extracts and the other potent nutraceuticals mentioned here now sits upon a strong scientific foundation.
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About the Author: Casey Adams, PhD, has more than two decades of natural foods and nutraceuticals industry experience, and a clinical practice in Watsonville, CA. He is also president of the consulting firm Realnatural, Inc., and the author of several books on natural health. His last article in Nutraceuticals World focused on the heart health market (November, 2009). He can be reached at ca@caseadams.com.