Sean Moloughney10.01.08
Alzheimer's disease has surpassed diabetes as the sixth-leading cause of death in the U.S. And with 10 million Baby Boomers expected to develop this progressive brain disorder in their lifetime, cognitive health has moved to the forefront of everyone's mind.
Direct and indirect costs of Alzheimer's and other forms of dementia amount to an estimated $148 billion a year-about the size of California's 2007 state budget. Worldwide, Alzheimer's currently affects 13 million people. An estimated 1 million Americans are also living with Parkinson's disease, and another quarter million either have or are at risk for inheriting Huntington's disease-both movement disorders with no known cure.
Alongside an aging population, a range of factors influencing market growth for brain health products include a competitive educational and work environment, greater understanding and acceptance of nutrition's role incognitive function, increased nutritional research, and the proliferation of supplement usage.
The market for nutritional supplements intended to enhance cognition grew 122% in 2002 and today exceeds $300 million, according to Peter Leighton, CEO of Kirkland, WA-based Advana Science, Inc., a biotechnology company holding a portfolio of patents applicable to nutraceuticals that reduce beta amyloid in the brain.
"At the core of Advana's intellectual property is the leading research and development work surrounding beta amyloid and the biological damage it wreaks," Mr. Leighton said. This neurotoxic protein forms insoluble fibrils, which lead to the formation of neural plaques in the brain, killing healthy neurons and leading to Alzheimer's disease (AD).
More specifically, amyloid buildup in the extra-cellular spaces within nerve tissue and in the blood vessel walls causes endothelial damage, resulting in cerebral amyloid angiopathy, which can rupture arteries and arterioles in the cortex. Such hemorrhages are often the cause of death for AD patients. Autopsies conducted on Alzheimer's victims show significantly reduced brain mass caused by a loss of nerve cells, synapses and dendrites, especially in the neocortex.
Alongside genetic predisposition for brain disorders and oxidative stress, some common lifestyle factors that lead to brain deterioration include poor nutrition and a lack of physical and mental exercise.
Cognitive decline ranks highest among Baby Boomer fears, according to Gregory Stephens, vice president of strategic consulting, Natural Marketing Institute (NMI), Harleysville, PA. "Half of Boomers have a fear of losing mental/brain capacity and being a burden on their family or loved ones as a result of their aging," he said.
According to NMI's 2007 Health & Wellness Trends Database, while 71% of the general population is concerned about memory loss, which is the same percentage concerned about cancer, only 13% say they are satisfied with how their household is currently managing this health condition, indicating significant opportunity for manufacturers of brain health ingredients. NMI also reports that 38% of consumers say they would use foods/beverages to prevent memory loss, and 35% say they would do the same to treat this condition.
So with the opportunity to alleviate the stressors associated with cognitive decline through dietary supplement and functional food consumption, which ingredients are leading the expanding market for brain health products, and what direction are researchers headed in an effort to support their efficacy?
Perhaps one of the brightest signs related to the growing need for brain-enhancing nutrients has been the focus on CoQ10, which is involved in cellular energy production, and has documented heart and neurological benefits.
Recently, the Huntington Study Group, Rochester, NY, launched a Phase III clinical trial to determine the impact of CoQ10's maximum effective dosage on cognitive function in people with Huntington's disease. It will be the largest therapeutic clinical trial to date focused on this genetic brain disorder.
KanekaQ10, manufactured by Pasadena, CA-based Kaneka Nutrients, will be used in the trial, which is funded by the National Institute of Neurological Disorders and Stroke-part of the National Institutes of Health (NIH). The five-year, double-blind, placebo-controlled study (called the 2CARE Study) will involve 608 patients in 44 centers across the U.S., Canada and Australia.
According to Kaneka Nutrients, its product is fermented from yeast and does not contain impurities found in synthetically processed CoQ10. It has also been self-affirmed GRAS (Generally Recognized as Safe) for use in foods and beverages.
Scott Steinford, president, ZMC-USA, The Woodlands, TX, said CoQ10 is one of the most studied and promising products for cognitive health. "When a shortage of CoQ10 occurs within the human body the first place it is realized is the heart. The second most affected organ is the brain," he said. "Numerous studies have been done involving CoQ10, demonstrating a slowing of progression in those with Parkinson's disease specifically."
"Another study on mice indicated the combination of CoQ10 and vitamin E improved the brain activity that was shown to be deficient in Alzheimer's disease patients," Mr. Steinford added.
Phosphatidylserine (PS), a naturally occurring nutrient found in all human cells, with the highest concentrations in brain tissue, also continues to demonstrate a positive impact on cognitive function.
Parris Kidd, a technical consultant for Science & Ingredients, Inc., Carlsbad, CA, notes that six double-blind trials have demonstrated the effectiveness of PS to relieve symptoms of AD, or prevent its onset.
"At daily doses of 200 mg to 300 mg for up to six months, PS consistently improved clinical global impression and activities of daily living," he wrote in an article recently published in the peer-reviewed journal Alternative Medicine Review. "In more mild cases, PS improved orientation, concentration, learning and memory for names, locations and recent events. In the largest trial, which involved 425 patients with moderate to severe cognitive loss, PS significantly improved memory, learning, motivation, socialization and general 'adaptability to the environment.'"
PS supports many cellular functions particularly important to the brain, forming new neurons (neurogenesis), synthesizing chemicals that enable nerve transmission, boosting blood flow to the brain and protecting it from oxidative stress and degeneration. It has also been connected to the activation of protein kinase C (PKC)-an enzyme complex critical to neuronal signal transduction and memory trace formation. "PKC dysfunction is one of the earliest changes noted in AD and is being investigated as a target for drug development," Dr. Kidd noted in his article.
In 2003, FDA granted two health claims for PS: "PS may reduce the risk of cognitive dysfunction in the elderly" and "PS may reduce the risk of dementia in the elderly."
According to Darren Schneider, director of sales and marketing with Ronkonkoma, NY-based CapsuleWorks, which supplies Neuro-PS derived from soy, recent research has focused on the ability of PS to affect cognitive performance in athletes. "Since PS can impact the body's response to stress by affecting the hypothalamus-pituitary-axis in the brain, studies have looked to see if this can reduce cortisol levels. The most recent study to look into this found that 600 mg per day of PS reduced cortisol levels in healthy males after moderately intense exercise," he said, referencing a study published recently in the Journal of the International Society of Sports Nutrition.
Science & Ingredients offers Omega PS in addition to its PS product and other phospholipids. "This is the new generation of PS nutraceuticals, featuring the PS molecule with omega 3 DHA and EPA built in," said the company's CEO Peter Rohde. "This molecular framework improves the bioavailability and bioactivity of these long-chain omega 3s, which are pivotal to brain development, maintenance and adaptability. Having both sets of nutraceuticals in the same molecule also facilitates their natural functional synergy in the brain."
Several other manufacturers have also recognized the synergistic potential of PS and omega 3s. Orly Farkash, marketing manager, Enzymotec, Migdal HaEmeq, Israel, said the company's Sharp-PS Gold, a patented, conjugated PS-DHA compound, "mimics the structure-function of human PS to better activate memory and mental performance while increasing DHA availability in the brain." The company also offers a "platinum grade" (40% DHA/EPA), as well as a PS ingredient extracted from soy.
According to Ms. Farkash, Enzymotec recently concluded an open-label pilot study in which 30 elderly subjects with memory complaints were treated with Enzymotec's Sharp-PS for 12 weeks. Subjects' cognitive performance was assessed using a computerized assessment battery and results showed Sharp-PS improved memory and attention parameters.
Neptune Krill Oil (NKO), manufactured by Neptune Technologies & Bioressources, Laval, Quebec, Canada, supplies essential omega 3 fatty acids (EPA and DHA) that are attached to phospholipids, which function as superior delivery systems due to their amphipathic nature, according to Neptune's Wael Massrieh, PhD, director of research and development. DHA is vital to proper brain development and maintenance and exerts its full cognitive benefits once made bioavailable and then delivered to the brain after crossing the blood-brain barrier, Mr. Massrieh noted, referring to a review by Dr. Kidd, which details the exceptional impact on cognition offered by omega 3s functionalized on phospholipids.
NKO also contains powerful antioxidants such as esterified astaxanthin and bioflavonoids, which offer protection against oxidation of the oil therefore providing additional stability and superiority, Mr. Massrieh said.
Omega 3s have also been tested in combination with other nutrients, including the potent antioxidant alpha lipoic acid. A recent randomized, double-blind, placebo-controlled study sponsored by the National Institute on Aging, a division of NIH, evaluated about 40 patients 55 years of age or older with mild AD. The one-year study conducted at Oregon Health and Science University compared the effect of taking fish oil alone to consuming fish oil in combination with alpha lipoic acid, which was meant to slow the body's breakdown of the oil. Results showed those taking fish oil combined with alpha lipoic acid performed better on memory tests.
Much like CoQ10, documented research indicates omega 3 DHA imparts cardiovascular and neurological benefits. Epidemiological studies indicate relatively high intake of this essential fatty acid is linked to lower risk of dementia incidence or progression, and correlates to slower cognitive decline over time.
DHA is instrumental in the function of brain cell membranes-important for the transmission of brain signals, said Patrick Luchsinger, marketing manager, North America, Lipid Nutrition, Channahon, IL, which manufactures Marinol DHA concentrates available in oil and powder formats for supplements, food and beverages. "By making cell membranes more fluid, omega 3 fatty acids improve communication between the brain cells."
Mr. Luchsinger said the market for brain health ingredients, and DHA in particular, is "in the growth stage of the product life cycle" and will continue to expand as consumers become increasingly aware of the benefits associated with DHA.
While only 12% of consumers associate DHA with cognitive/brain health, this figure is up from just 4% in 2006, according to NMI's 2007 data. Omega 3s (22%) and antioxidants (22%) top the list of ingredients consumers associate with brain health, followed by "fish oil" (18%) and vitamin E (13%). (See Figure 3.)
NMI's Mr. Stephens said consumer awareness is increasing due in part to media coverage regarding efficacy and efforts from nutraceutical companies and trade associations to build branded ingredients.
Baldur Hjaltason, sales manager, North America, Japan and China, with Aalesund, Norway-based EPAX, said his company has focused its research on the critical role DHA plays in the elderly. "This can be compared to the role of calcium," he said. "We know we need calcium when we are young to build our bones, but now we also know that calcium is needed our entire lives to keep the bones healthy."
EPAX won an award from NIH for one of the two best scientific works related to dietary supplements and cognitive health in 2007.
With research ongoing, ingredient suppliers have focused on incorporating higher concentrations of omega 3s in their products. For example, EPAX 1050TG contains a minimum of 430 mg/g of DHA.
DSM Nutritional Products, Inc., Parsippany, NJ, also manufacturers highly concentrated omega 3 ingredients, offering ROPUFA omega 3 oils, powders and emulsions for use in supplements, food and beverages. DSM's Doug Brown, senior marketing manager, said an NIH Alzheimer's study currently underway is due in 2010. "Should the results confirm a greatly reduced risk of contracting Alzheimer's disease by supplementing with omega 3s, it will greatly impact consumer demand," he predicted.
Lori Covert, vice president of marketing and communications, Ocean Nutrition Canada, Dartmouth, Nova Scotia, Canada, said studies are also now focusing on the specific health benefits of EPA. "Results show EPA not only provides health benefits on its own, but also increases the efficacy of DHA," she said. "The combination of EPA and DHA together is greater than the sum of its parts. Research indicates EPA may ameliorate the onset and symptoms of Alzheimer's and dementia, and may also improve autoimmune disorders and cognition, as well as mood disorders, such as depression and schizophrenia."
Science & Ingredient's Dr. Kidd noted that while several researched nutrients have shown significant efficacy and safety, "the diagnosis of AD comes at such an advanced stage of neurodegeneration, and the disease progression is so unremitting, that chances for its eventual effective management seem remote." However, there is still reason for optimism with new early detection and prevention techniques.
Thus, the market for nutrients that maintain brain health throughout the lifespan, before age-related decline of cognitive function sets in, seems critical.
Karen Todd, RD, director of marketing, with New York, NY-based Kyowa Hakko USA, Inc. says clinical and laboratory research indicates Cognizin, the company's patented, proprietary form of citicoline, supports memory function and healthy cognition.
"Being a multi-functional ingredient, Cognizin has consistently delivered multiple benefits-increasing the brain's cell signaling (Ach, dopamine), cell integrity (phospholipids) and cell energy (ATP) levels," she noted.
A recent study conducted at McLean Hospital, an affiliate of Harvard Medical School, showed increased levels of the high-energy phosphate adenosine triphosphate (ATP) in the frontal cortex after six weeks of administering Cognizin to healthy volunteers. "This observation is also consistent with a treatment-related improvement in mitochondrial function," said Ms. Todd.
Neuroimaging data showed increased concentration, focus and improved accuracy, better performance and improved speed on cognitive tasks.
"Increasing ATP levels can enhance one's ability to mentally focus, concentrate and generally get work done," Ms. Todd said. "This is important because the frontal lobe is the highest 'executive branch' of the brain, directing complex thought, decision-making and attention. Scientists believe that citicoline's capacity to increase frontal lobe bioenergetics may be one of the reasons why this compound has shown success in improving cognitive function in older people."
Acetyl-L-carnitine (ALC), the acetyl derivative of L-carnitine, is another "smart compound" important for energetics in the brain and other tissues. ALC transports fatty acids from the cell cytoplasm into the mitochondria where they provide substrate for ATP generation via oxidative phosphorylation. Several clinical trials have found that ALC supplementation delays the progression of AD, improves memory and enhances overall performance in some people with the disease. Overall, most short-term studies have shown clinical benefits, and most long-term studies have shown a reduction in the rate of deterioration.
According to Matt Phillips, president and COO of Irvine, CA-based Cyvex Nutrition, the company's BioVinca vinpocetine, derived from the lesser periwinkle (Vinca minor L.), is a cerebral vasodilator and metabolic enhancer that improves blood flow to the brain by altering the rheological properties of blood.
"This makes vinpocetine of particular therapeutic use in treating a myriad of illnesses associated with insufficient blood flow to the brain," Mr. Phillips said. "In addition, vinpocetine is a Ca2+-dependent phosphodiesterase inhibitor. Phosphodiesterase is responsible for breaking down ATP, the primary energy 'currency' of all cells. As inhibition is specific to the brain, this results in a localized increase in energy available to neurons."
Easton, PA-based Linnea Inc., which has manufacturing facilities in Riazzino (Locarno) Switzerland, also supplies vinpocetine. Don Stanek, director of sales, said the ingredient "is believed to increase cerebral blood flow without significantly affecting systemic blood pressure, and in a wide series of studies has shown no serious side effects."
Still, Cal Bewicke, president of Ethical Naturals, San Anselmo, CA, which supplies a variety of botanical extracts, believes ginkgo biloba is the most prominent botanical in supporting long-term mental acuity. "To correspond with the long history of clinical success with this product, a very high level of quality control is required," he noted. "This includes the quantities and ratios of flavoneglycosides, and other control points to assure that the material has not in any way been diluted or adulterated with other compounds."
He went on to say that research on ginkgo has been consistent over the last 25 years, with more than 120 published studies, many of which validate its ability to support microcapilliary circulation in the brain.
Linnea also supplies pharmaceutical grade ginkgo biloba. According to the company's website, "The most common usage of ginkgo biloba extract is for its widely accepted effects in the regulation of blood flow to the brain, legs and other extremities. It is also commonly cited for controlling the level of various neurotransmitters in the brain thus helping to counteract memory loss, depression and lack of alertness, which may occur in old age. As a 'smart drug' ginkgo biloba extract may also promote the metabolism of cerebral and neurosensorial cells."
Linnea's Mr. Stanek said there are many inferior extracts on the market that have similar specifications, but not the total content and balance of the constituent ingredients that make the product biologically active. "Linnea's Ginkgo Biloba Extract EPG 246 complies with the German and American monographs (the reference standard qualities upon which the majority of research has been carried out) and the European pharmacopoeia (a current working project)."
Antoine Dauby, group marketing manager, Naturex, Avignon, France, said he believes mental health is one of the most promising areas in the global nutraceutical market. Demonstrating its commitment to this segment, the company has entered into an agreement with the Brain Science Institute (BSI) at Swinburne University in Melbourne, Australia to validate the cognitive enhancement capacity of Naturex's strategic botanical extracts with gluco-regulatory capacity. The company's product portfolio includes ginseng, rhodiola, rosemary, guarana, yerba mate, Fraxinus excelsior and Spergularia purpurea.
This three-and-a-half-year project intends to build on research that links circulating blood glucose and cognitive performance. It is expected to yield seven randomized, double-blind, placebo-controlled clinical trials, according to Mr. Dauby. "It will allow us to establish the optimum cognition-enhancing dose and to determine which cognitive domains are the most affected by each botanical extract."
Naturex is also involved in a project called "New Technologies for Ginseng Agriculture and Product Development," which intends to validate several health claims on North American ginseng. Researchers will focus on various medical and health areas, including neuroprotective and psychiatric disorders.
In other developments, recent studies have pointed to the promising effects of an ancient traditional Chinese herbal medicine known as Chinese club moss extract (Huperzine A) on AD patients. A recent meta-analysis that reviewed data from six trials involving 454 subjects concluded that AD patients taking Huperzine A showed improved general cognitive function, global clinical status, functional performance and reduced behavioral disturbance compared to those taking placebos. Huperzine A blocks acetylcholinesterase (ACE), which breaks down acetylcholine.
Recent research also links the consumption of black tea to reduced risk of Parkinson's. A National Neuroscience Institute study published in the American Journal of Epidemiology looked at disease prevalence among 63,000 Chinese men and women, comparing their intake of certain beverages. The study found those who drank at least 23 cups of black tea a month were 71% less likely to develop Parkinson's. Black tea contains antioxidant polyphenols (catechins, flavonols, theaflavins and thearubigins), which are believed to offer protection from Parkinson's.
Curcumin is also making a strong impression on the industry, with a growing body of evidence supporting its ability to enhance beta amyloid uptake. Curcumin C3 Complex, a branded "bioprotectant" antioxidant composition of curcuminoids from Sabinsa Corporation, Piscataway, NJ, was used in research by UCLA, and was found to help prevent AD and dementia. Further research is in progress, according to Lakshmi Prakash, PhD, vice president, Innovation & Business Development.
"The role of curcuminoids as an antioxidant and anti-inflammatory agent is well established," said Ms. Prakash. "Additionally, curcuminoids have anti-thrombotic activity and prevent platelet aggregation, with potential benefits in supporting cardiovascular health/healthy blood circulation, which is important in preventing strokes, for example."
Grape seed extract is another ingredient that shows promise in preventing cognitive decline. Researchers at Mount Sinai School of Medicine collaborated with UCLA's Molecular Biology Institute and the director of the Polyphenolics division of Constellation Brands, Madera, CA-a major producer of biologically active grape products-to test the hypothesis that certain molecules contained in red wine, specifically in grape seeds currently being developed under the name of MegaNatural-AZ, might offset disease progression in mice genetically modified to develop Alzheimer's.
Results published in the Journal of Neuroscience showed supplementation of MegaNatural-AZ reduced AD-type cognitive deterioration through mechanisms that prevent the formation of amyloid in the brain.
"Polyphenolics continues to fund further research at Mount Sinai to explore the science," said Anil Shrikhande, PhD, president of Polyphenolics. "Data are very convincing with animal models and supporting in vitro and other tests that MegaNatural-AZ may prevent cognitive decline in certain population segments, such as Baby Boomers. I am personally fascinated by these prospects and feel extremely hopeful of this innovation. Patents are pending for applications and composition."
Pine bark extract is another potent antioxidant with recent research demonstrating its potential to support brain health. Researchers at the Brain Sciences Institute of Swinburne University in Melbourne, Australia, investigated the cognitive effects of Enzogenol pine bark extract-from Enzo Nutraceuticals Ltd., Waihi Beach, New Zealand-through a double-blind, placebo-controlled trial of 42 men, ages 50 to 65. Results published in Phytotherapy Research indicated that after five weeks of high dose Enzogenol treatment (960 mg/day) participants significantly improved performance on immediate recognition and spatial working memory tests.
"These are important brain functions that are constantly used in many activities, for example, when driving a car, when working on the computer or in any physical and sports activities," said Matt Frevel, PhD, chief science officer, Enzo Nutraceuticals. "These working memory functions have been shown to naturally decline with age. The mechanism of action by which Enzogenol may cause these improvements needs further study. Mechanisms may include improving cerebral blood circulation, directly influencing neuronal signal transduction and decreasing oxidative damage in the brain."
Overall, Paul Altaffer, vice president, Business and Product Development, RFI Ingredients, Blauvelt NY, sees the science behind brain health developing very quickly. "Traditional cognitive studies can now be correlated to other techniques, including anatomical views of the brain (through PET scans and MRIs)," he said. "The interest and availability of new research tools will make this one of the most promising areas of new science in the field of nutrition and natural therapies."
He predicted continued growth for this "ripe market," for a long time to come. "As Baby Boomers near retirement age, yet sustain active lifestyles, maintaining or improving cognitive function will be an important goal. Likewise, younger generations that feel pressure for high performance in cognitive function, this too will generate many opportunities for product developers looking to capitalize on this industry segment."
Currently, RFI offers cocoa-derived Chocamine, which contains a variety of neurochemicals, including theobromine, biogenic amines and anandamides. It also supplies its Oxyphyte line of antioxidants.
Various vitamins that have gained mainstream popularity among consumers have also been linked to positive impacts on important brain functions.
Todd Sitkowski, a senior marketing manager with DSM Nutritional Products, said B complex vitamins, mainly B1, B2 and B6, as well as niacin, are needed for synthesis of neurotransmitters, which support mental performance and learning capacity. "Folic acid and B12 may also improve mood and reduce symptoms of depression in the elderly," he said.
Researchers at England's Oxford University recently concluded that consuming more vitamin B12 may prevent brain shrinkage and memory loss later in life. Of 107 study subjects (ages 61 to 87), who did not have any brain disorders, those with the highest B12 levels were six times less likely to have brain shrinkage compared to those with lower levels.
ZMC-USA's Mr. Steinford said vitamin E may also slow the progression of cognitive failure. "In a six-year study at Rush University in Chicago, cognitive decline in AD was associated with low intake of vitamin E, alpha-tocopherols and gamma-tocopherols. In a cohort of 1033 elderly people, Italian researchers found participants with low plasma vitamin E levels had a significantly higher probability of suffering from dementia and cognitive impairment, compared to those with high levels of vitamin E."
Alongside B vitamins and vitamin E, the carotenoid beta-carotene has been shown to help protect against cognitive decline associated with aging, according to Mr. Sitkowski. "Beta-carotene provides long-term benefits to memory and may significantly help to preserve mental fitness," he said, citing "The Physicians Health Study I and II," initiated in the 1980s.
BASF, Florham Park, NJ, supplies a broad range of health ingredients, including beta-carotene-suitable for various applications-along with B vitamins and vitamin E, which according to the company, "display excellent properties for use in the tableting process: high flowability, low dusting, proper bulk density, excellent compactability and quick release of active ingredients." The company also offers a line of microencapsulated fish oils rich in EPA and DHA.
Direct and indirect costs of Alzheimer's and other forms of dementia amount to an estimated $148 billion a year-about the size of California's 2007 state budget. Worldwide, Alzheimer's currently affects 13 million people. An estimated 1 million Americans are also living with Parkinson's disease, and another quarter million either have or are at risk for inheriting Huntington's disease-both movement disorders with no known cure.
Alongside an aging population, a range of factors influencing market growth for brain health products include a competitive educational and work environment, greater understanding and acceptance of nutrition's role incognitive function, increased nutritional research, and the proliferation of supplement usage.
A Market Ripe for Growth
The market for nutritional supplements intended to enhance cognition grew 122% in 2002 and today exceeds $300 million, according to Peter Leighton, CEO of Kirkland, WA-based Advana Science, Inc., a biotechnology company holding a portfolio of patents applicable to nutraceuticals that reduce beta amyloid in the brain.
"At the core of Advana's intellectual property is the leading research and development work surrounding beta amyloid and the biological damage it wreaks," Mr. Leighton said. This neurotoxic protein forms insoluble fibrils, which lead to the formation of neural plaques in the brain, killing healthy neurons and leading to Alzheimer's disease (AD).
More specifically, amyloid buildup in the extra-cellular spaces within nerve tissue and in the blood vessel walls causes endothelial damage, resulting in cerebral amyloid angiopathy, which can rupture arteries and arterioles in the cortex. Such hemorrhages are often the cause of death for AD patients. Autopsies conducted on Alzheimer's victims show significantly reduced brain mass caused by a loss of nerve cells, synapses and dendrites, especially in the neocortex.
Alongside genetic predisposition for brain disorders and oxidative stress, some common lifestyle factors that lead to brain deterioration include poor nutrition and a lack of physical and mental exercise.
Cognitive decline ranks highest among Baby Boomer fears, according to Gregory Stephens, vice president of strategic consulting, Natural Marketing Institute (NMI), Harleysville, PA. "Half of Boomers have a fear of losing mental/brain capacity and being a burden on their family or loved ones as a result of their aging," he said.
According to NMI's 2007 Health & Wellness Trends Database, while 71% of the general population is concerned about memory loss, which is the same percentage concerned about cancer, only 13% say they are satisfied with how their household is currently managing this health condition, indicating significant opportunity for manufacturers of brain health ingredients. NMI also reports that 38% of consumers say they would use foods/beverages to prevent memory loss, and 35% say they would do the same to treat this condition.
So with the opportunity to alleviate the stressors associated with cognitive decline through dietary supplement and functional food consumption, which ingredients are leading the expanding market for brain health products, and what direction are researchers headed in an effort to support their efficacy?
CoQ10
Perhaps one of the brightest signs related to the growing need for brain-enhancing nutrients has been the focus on CoQ10, which is involved in cellular energy production, and has documented heart and neurological benefits.
Recently, the Huntington Study Group, Rochester, NY, launched a Phase III clinical trial to determine the impact of CoQ10's maximum effective dosage on cognitive function in people with Huntington's disease. It will be the largest therapeutic clinical trial to date focused on this genetic brain disorder.
KanekaQ10, manufactured by Pasadena, CA-based Kaneka Nutrients, will be used in the trial, which is funded by the National Institute of Neurological Disorders and Stroke-part of the National Institutes of Health (NIH). The five-year, double-blind, placebo-controlled study (called the 2CARE Study) will involve 608 patients in 44 centers across the U.S., Canada and Australia.
According to Kaneka Nutrients, its product is fermented from yeast and does not contain impurities found in synthetically processed CoQ10. It has also been self-affirmed GRAS (Generally Recognized as Safe) for use in foods and beverages.
Scott Steinford, president, ZMC-USA, The Woodlands, TX, said CoQ10 is one of the most studied and promising products for cognitive health. "When a shortage of CoQ10 occurs within the human body the first place it is realized is the heart. The second most affected organ is the brain," he said. "Numerous studies have been done involving CoQ10, demonstrating a slowing of progression in those with Parkinson's disease specifically."
"Another study on mice indicated the combination of CoQ10 and vitamin E improved the brain activity that was shown to be deficient in Alzheimer's disease patients," Mr. Steinford added.
The Power of PS
Phosphatidylserine (PS), a naturally occurring nutrient found in all human cells, with the highest concentrations in brain tissue, also continues to demonstrate a positive impact on cognitive function.
Parris Kidd, a technical consultant for Science & Ingredients, Inc., Carlsbad, CA, notes that six double-blind trials have demonstrated the effectiveness of PS to relieve symptoms of AD, or prevent its onset.
"At daily doses of 200 mg to 300 mg for up to six months, PS consistently improved clinical global impression and activities of daily living," he wrote in an article recently published in the peer-reviewed journal Alternative Medicine Review. "In more mild cases, PS improved orientation, concentration, learning and memory for names, locations and recent events. In the largest trial, which involved 425 patients with moderate to severe cognitive loss, PS significantly improved memory, learning, motivation, socialization and general 'adaptability to the environment.'"
PS supports many cellular functions particularly important to the brain, forming new neurons (neurogenesis), synthesizing chemicals that enable nerve transmission, boosting blood flow to the brain and protecting it from oxidative stress and degeneration. It has also been connected to the activation of protein kinase C (PKC)-an enzyme complex critical to neuronal signal transduction and memory trace formation. "PKC dysfunction is one of the earliest changes noted in AD and is being investigated as a target for drug development," Dr. Kidd noted in his article.
In 2003, FDA granted two health claims for PS: "PS may reduce the risk of cognitive dysfunction in the elderly" and "PS may reduce the risk of dementia in the elderly."
According to Darren Schneider, director of sales and marketing with Ronkonkoma, NY-based CapsuleWorks, which supplies Neuro-PS derived from soy, recent research has focused on the ability of PS to affect cognitive performance in athletes. "Since PS can impact the body's response to stress by affecting the hypothalamus-pituitary-axis in the brain, studies have looked to see if this can reduce cortisol levels. The most recent study to look into this found that 600 mg per day of PS reduced cortisol levels in healthy males after moderately intense exercise," he said, referencing a study published recently in the Journal of the International Society of Sports Nutrition.
Strength through Synergy
Science & Ingredients offers Omega PS in addition to its PS product and other phospholipids. "This is the new generation of PS nutraceuticals, featuring the PS molecule with omega 3 DHA and EPA built in," said the company's CEO Peter Rohde. "This molecular framework improves the bioavailability and bioactivity of these long-chain omega 3s, which are pivotal to brain development, maintenance and adaptability. Having both sets of nutraceuticals in the same molecule also facilitates their natural functional synergy in the brain."
Several other manufacturers have also recognized the synergistic potential of PS and omega 3s. Orly Farkash, marketing manager, Enzymotec, Migdal HaEmeq, Israel, said the company's Sharp-PS Gold, a patented, conjugated PS-DHA compound, "mimics the structure-function of human PS to better activate memory and mental performance while increasing DHA availability in the brain." The company also offers a "platinum grade" (40% DHA/EPA), as well as a PS ingredient extracted from soy.
According to Ms. Farkash, Enzymotec recently concluded an open-label pilot study in which 30 elderly subjects with memory complaints were treated with Enzymotec's Sharp-PS for 12 weeks. Subjects' cognitive performance was assessed using a computerized assessment battery and results showed Sharp-PS improved memory and attention parameters.
Neptune Krill Oil (NKO), manufactured by Neptune Technologies & Bioressources, Laval, Quebec, Canada, supplies essential omega 3 fatty acids (EPA and DHA) that are attached to phospholipids, which function as superior delivery systems due to their amphipathic nature, according to Neptune's Wael Massrieh, PhD, director of research and development. DHA is vital to proper brain development and maintenance and exerts its full cognitive benefits once made bioavailable and then delivered to the brain after crossing the blood-brain barrier, Mr. Massrieh noted, referring to a review by Dr. Kidd, which details the exceptional impact on cognition offered by omega 3s functionalized on phospholipids.
NKO also contains powerful antioxidants such as esterified astaxanthin and bioflavonoids, which offer protection against oxidation of the oil therefore providing additional stability and superiority, Mr. Massrieh said.
Omega 3s have also been tested in combination with other nutrients, including the potent antioxidant alpha lipoic acid. A recent randomized, double-blind, placebo-controlled study sponsored by the National Institute on Aging, a division of NIH, evaluated about 40 patients 55 years of age or older with mild AD. The one-year study conducted at Oregon Health and Science University compared the effect of taking fish oil alone to consuming fish oil in combination with alpha lipoic acid, which was meant to slow the body's breakdown of the oil. Results showed those taking fish oil combined with alpha lipoic acid performed better on memory tests.
Omega 3s on the Upswing
Much like CoQ10, documented research indicates omega 3 DHA imparts cardiovascular and neurological benefits. Epidemiological studies indicate relatively high intake of this essential fatty acid is linked to lower risk of dementia incidence or progression, and correlates to slower cognitive decline over time.
DHA is instrumental in the function of brain cell membranes-important for the transmission of brain signals, said Patrick Luchsinger, marketing manager, North America, Lipid Nutrition, Channahon, IL, which manufactures Marinol DHA concentrates available in oil and powder formats for supplements, food and beverages. "By making cell membranes more fluid, omega 3 fatty acids improve communication between the brain cells."
Mr. Luchsinger said the market for brain health ingredients, and DHA in particular, is "in the growth stage of the product life cycle" and will continue to expand as consumers become increasingly aware of the benefits associated with DHA.
While only 12% of consumers associate DHA with cognitive/brain health, this figure is up from just 4% in 2006, according to NMI's 2007 data. Omega 3s (22%) and antioxidants (22%) top the list of ingredients consumers associate with brain health, followed by "fish oil" (18%) and vitamin E (13%). (See Figure 3.)
NMI's Mr. Stephens said consumer awareness is increasing due in part to media coverage regarding efficacy and efforts from nutraceutical companies and trade associations to build branded ingredients.
Baldur Hjaltason, sales manager, North America, Japan and China, with Aalesund, Norway-based EPAX, said his company has focused its research on the critical role DHA plays in the elderly. "This can be compared to the role of calcium," he said. "We know we need calcium when we are young to build our bones, but now we also know that calcium is needed our entire lives to keep the bones healthy."
EPAX won an award from NIH for one of the two best scientific works related to dietary supplements and cognitive health in 2007.
With research ongoing, ingredient suppliers have focused on incorporating higher concentrations of omega 3s in their products. For example, EPAX 1050TG contains a minimum of 430 mg/g of DHA.
DSM Nutritional Products, Inc., Parsippany, NJ, also manufacturers highly concentrated omega 3 ingredients, offering ROPUFA omega 3 oils, powders and emulsions for use in supplements, food and beverages. DSM's Doug Brown, senior marketing manager, said an NIH Alzheimer's study currently underway is due in 2010. "Should the results confirm a greatly reduced risk of contracting Alzheimer's disease by supplementing with omega 3s, it will greatly impact consumer demand," he predicted.
Lori Covert, vice president of marketing and communications, Ocean Nutrition Canada, Dartmouth, Nova Scotia, Canada, said studies are also now focusing on the specific health benefits of EPA. "Results show EPA not only provides health benefits on its own, but also increases the efficacy of DHA," she said. "The combination of EPA and DHA together is greater than the sum of its parts. Research indicates EPA may ameliorate the onset and symptoms of Alzheimer's and dementia, and may also improve autoimmune disorders and cognition, as well as mood disorders, such as depression and schizophrenia."
'Smart' Compounds
Science & Ingredient's Dr. Kidd noted that while several researched nutrients have shown significant efficacy and safety, "the diagnosis of AD comes at such an advanced stage of neurodegeneration, and the disease progression is so unremitting, that chances for its eventual effective management seem remote." However, there is still reason for optimism with new early detection and prevention techniques.
Thus, the market for nutrients that maintain brain health throughout the lifespan, before age-related decline of cognitive function sets in, seems critical.
Karen Todd, RD, director of marketing, with New York, NY-based Kyowa Hakko USA, Inc. says clinical and laboratory research indicates Cognizin, the company's patented, proprietary form of citicoline, supports memory function and healthy cognition.
"Being a multi-functional ingredient, Cognizin has consistently delivered multiple benefits-increasing the brain's cell signaling (Ach, dopamine), cell integrity (phospholipids) and cell energy (ATP) levels," she noted.
A recent study conducted at McLean Hospital, an affiliate of Harvard Medical School, showed increased levels of the high-energy phosphate adenosine triphosphate (ATP) in the frontal cortex after six weeks of administering Cognizin to healthy volunteers. "This observation is also consistent with a treatment-related improvement in mitochondrial function," said Ms. Todd.
Neuroimaging data showed increased concentration, focus and improved accuracy, better performance and improved speed on cognitive tasks.
"Increasing ATP levels can enhance one's ability to mentally focus, concentrate and generally get work done," Ms. Todd said. "This is important because the frontal lobe is the highest 'executive branch' of the brain, directing complex thought, decision-making and attention. Scientists believe that citicoline's capacity to increase frontal lobe bioenergetics may be one of the reasons why this compound has shown success in improving cognitive function in older people."
Acetyl-L-carnitine (ALC), the acetyl derivative of L-carnitine, is another "smart compound" important for energetics in the brain and other tissues. ALC transports fatty acids from the cell cytoplasm into the mitochondria where they provide substrate for ATP generation via oxidative phosphorylation. Several clinical trials have found that ALC supplementation delays the progression of AD, improves memory and enhances overall performance in some people with the disease. Overall, most short-term studies have shown clinical benefits, and most long-term studies have shown a reduction in the rate of deterioration.
Botanicals & Antioxidants
According to Matt Phillips, president and COO of Irvine, CA-based Cyvex Nutrition, the company's BioVinca vinpocetine, derived from the lesser periwinkle (Vinca minor L.), is a cerebral vasodilator and metabolic enhancer that improves blood flow to the brain by altering the rheological properties of blood.
"This makes vinpocetine of particular therapeutic use in treating a myriad of illnesses associated with insufficient blood flow to the brain," Mr. Phillips said. "In addition, vinpocetine is a Ca2+-dependent phosphodiesterase inhibitor. Phosphodiesterase is responsible for breaking down ATP, the primary energy 'currency' of all cells. As inhibition is specific to the brain, this results in a localized increase in energy available to neurons."
Easton, PA-based Linnea Inc., which has manufacturing facilities in Riazzino (Locarno) Switzerland, also supplies vinpocetine. Don Stanek, director of sales, said the ingredient "is believed to increase cerebral blood flow without significantly affecting systemic blood pressure, and in a wide series of studies has shown no serious side effects."
Still, Cal Bewicke, president of Ethical Naturals, San Anselmo, CA, which supplies a variety of botanical extracts, believes ginkgo biloba is the most prominent botanical in supporting long-term mental acuity. "To correspond with the long history of clinical success with this product, a very high level of quality control is required," he noted. "This includes the quantities and ratios of flavoneglycosides, and other control points to assure that the material has not in any way been diluted or adulterated with other compounds."
He went on to say that research on ginkgo has been consistent over the last 25 years, with more than 120 published studies, many of which validate its ability to support microcapilliary circulation in the brain.
Linnea also supplies pharmaceutical grade ginkgo biloba. According to the company's website, "The most common usage of ginkgo biloba extract is for its widely accepted effects in the regulation of blood flow to the brain, legs and other extremities. It is also commonly cited for controlling the level of various neurotransmitters in the brain thus helping to counteract memory loss, depression and lack of alertness, which may occur in old age. As a 'smart drug' ginkgo biloba extract may also promote the metabolism of cerebral and neurosensorial cells."
Linnea's Mr. Stanek said there are many inferior extracts on the market that have similar specifications, but not the total content and balance of the constituent ingredients that make the product biologically active. "Linnea's Ginkgo Biloba Extract EPG 246 complies with the German and American monographs (the reference standard qualities upon which the majority of research has been carried out) and the European pharmacopoeia (a current working project)."
Antoine Dauby, group marketing manager, Naturex, Avignon, France, said he believes mental health is one of the most promising areas in the global nutraceutical market. Demonstrating its commitment to this segment, the company has entered into an agreement with the Brain Science Institute (BSI) at Swinburne University in Melbourne, Australia to validate the cognitive enhancement capacity of Naturex's strategic botanical extracts with gluco-regulatory capacity. The company's product portfolio includes ginseng, rhodiola, rosemary, guarana, yerba mate, Fraxinus excelsior and Spergularia purpurea.
This three-and-a-half-year project intends to build on research that links circulating blood glucose and cognitive performance. It is expected to yield seven randomized, double-blind, placebo-controlled clinical trials, according to Mr. Dauby. "It will allow us to establish the optimum cognition-enhancing dose and to determine which cognitive domains are the most affected by each botanical extract."
Naturex is also involved in a project called "New Technologies for Ginseng Agriculture and Product Development," which intends to validate several health claims on North American ginseng. Researchers will focus on various medical and health areas, including neuroprotective and psychiatric disorders.
In other developments, recent studies have pointed to the promising effects of an ancient traditional Chinese herbal medicine known as Chinese club moss extract (Huperzine A) on AD patients. A recent meta-analysis that reviewed data from six trials involving 454 subjects concluded that AD patients taking Huperzine A showed improved general cognitive function, global clinical status, functional performance and reduced behavioral disturbance compared to those taking placebos. Huperzine A blocks acetylcholinesterase (ACE), which breaks down acetylcholine.
Recent research also links the consumption of black tea to reduced risk of Parkinson's. A National Neuroscience Institute study published in the American Journal of Epidemiology looked at disease prevalence among 63,000 Chinese men and women, comparing their intake of certain beverages. The study found those who drank at least 23 cups of black tea a month were 71% less likely to develop Parkinson's. Black tea contains antioxidant polyphenols (catechins, flavonols, theaflavins and thearubigins), which are believed to offer protection from Parkinson's.
Curcumin is also making a strong impression on the industry, with a growing body of evidence supporting its ability to enhance beta amyloid uptake. Curcumin C3 Complex, a branded "bioprotectant" antioxidant composition of curcuminoids from Sabinsa Corporation, Piscataway, NJ, was used in research by UCLA, and was found to help prevent AD and dementia. Further research is in progress, according to Lakshmi Prakash, PhD, vice president, Innovation & Business Development.
"The role of curcuminoids as an antioxidant and anti-inflammatory agent is well established," said Ms. Prakash. "Additionally, curcuminoids have anti-thrombotic activity and prevent platelet aggregation, with potential benefits in supporting cardiovascular health/healthy blood circulation, which is important in preventing strokes, for example."
Grape seed extract is another ingredient that shows promise in preventing cognitive decline. Researchers at Mount Sinai School of Medicine collaborated with UCLA's Molecular Biology Institute and the director of the Polyphenolics division of Constellation Brands, Madera, CA-a major producer of biologically active grape products-to test the hypothesis that certain molecules contained in red wine, specifically in grape seeds currently being developed under the name of MegaNatural-AZ, might offset disease progression in mice genetically modified to develop Alzheimer's.
Results published in the Journal of Neuroscience showed supplementation of MegaNatural-AZ reduced AD-type cognitive deterioration through mechanisms that prevent the formation of amyloid in the brain.
"Polyphenolics continues to fund further research at Mount Sinai to explore the science," said Anil Shrikhande, PhD, president of Polyphenolics. "Data are very convincing with animal models and supporting in vitro and other tests that MegaNatural-AZ may prevent cognitive decline in certain population segments, such as Baby Boomers. I am personally fascinated by these prospects and feel extremely hopeful of this innovation. Patents are pending for applications and composition."
Pine bark extract is another potent antioxidant with recent research demonstrating its potential to support brain health. Researchers at the Brain Sciences Institute of Swinburne University in Melbourne, Australia, investigated the cognitive effects of Enzogenol pine bark extract-from Enzo Nutraceuticals Ltd., Waihi Beach, New Zealand-through a double-blind, placebo-controlled trial of 42 men, ages 50 to 65. Results published in Phytotherapy Research indicated that after five weeks of high dose Enzogenol treatment (960 mg/day) participants significantly improved performance on immediate recognition and spatial working memory tests.
"These are important brain functions that are constantly used in many activities, for example, when driving a car, when working on the computer or in any physical and sports activities," said Matt Frevel, PhD, chief science officer, Enzo Nutraceuticals. "These working memory functions have been shown to naturally decline with age. The mechanism of action by which Enzogenol may cause these improvements needs further study. Mechanisms may include improving cerebral blood circulation, directly influencing neuronal signal transduction and decreasing oxidative damage in the brain."
Overall, Paul Altaffer, vice president, Business and Product Development, RFI Ingredients, Blauvelt NY, sees the science behind brain health developing very quickly. "Traditional cognitive studies can now be correlated to other techniques, including anatomical views of the brain (through PET scans and MRIs)," he said. "The interest and availability of new research tools will make this one of the most promising areas of new science in the field of nutrition and natural therapies."
He predicted continued growth for this "ripe market," for a long time to come. "As Baby Boomers near retirement age, yet sustain active lifestyles, maintaining or improving cognitive function will be an important goal. Likewise, younger generations that feel pressure for high performance in cognitive function, this too will generate many opportunities for product developers looking to capitalize on this industry segment."
Currently, RFI offers cocoa-derived Chocamine, which contains a variety of neurochemicals, including theobromine, biogenic amines and anandamides. It also supplies its Oxyphyte line of antioxidants.
Vitamins
Various vitamins that have gained mainstream popularity among consumers have also been linked to positive impacts on important brain functions.
Todd Sitkowski, a senior marketing manager with DSM Nutritional Products, said B complex vitamins, mainly B1, B2 and B6, as well as niacin, are needed for synthesis of neurotransmitters, which support mental performance and learning capacity. "Folic acid and B12 may also improve mood and reduce symptoms of depression in the elderly," he said.
Researchers at England's Oxford University recently concluded that consuming more vitamin B12 may prevent brain shrinkage and memory loss later in life. Of 107 study subjects (ages 61 to 87), who did not have any brain disorders, those with the highest B12 levels were six times less likely to have brain shrinkage compared to those with lower levels.
ZMC-USA's Mr. Steinford said vitamin E may also slow the progression of cognitive failure. "In a six-year study at Rush University in Chicago, cognitive decline in AD was associated with low intake of vitamin E, alpha-tocopherols and gamma-tocopherols. In a cohort of 1033 elderly people, Italian researchers found participants with low plasma vitamin E levels had a significantly higher probability of suffering from dementia and cognitive impairment, compared to those with high levels of vitamin E."
Alongside B vitamins and vitamin E, the carotenoid beta-carotene has been shown to help protect against cognitive decline associated with aging, according to Mr. Sitkowski. "Beta-carotene provides long-term benefits to memory and may significantly help to preserve mental fitness," he said, citing "The Physicians Health Study I and II," initiated in the 1980s.
BASF, Florham Park, NJ, supplies a broad range of health ingredients, including beta-carotene-suitable for various applications-along with B vitamins and vitamin E, which according to the company, "display excellent properties for use in the tableting process: high flowability, low dusting, proper bulk density, excellent compactability and quick release of active ingredients." The company also offers a line of microencapsulated fish oils rich in EPA and DHA.