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I N O R T H O M O L E C U L A R R E S E A R C H
VOLUME 4 ISSUE 4

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O R T H O M O L E C U L A R

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I N O R T H O M O L E C U L A R R E S E A R C H

Cognitive Health
I N O R T H O M O L E C U L A R

R E S E A R C H

Use Your Mind, Dont Lose It

I N O R T H O M O L E C U L A R
RESEARCH-DRIVEN BOTANICAL INTEGRATIVE

ADVANCES
R E S E A R C H
ORTHOMOLECULAR INNOVATIVE

FR EE

Supports the Hippocampus

Time Remember
1.800.387.0177 www.ovos.ca

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Memory and Cognitive Performance Cognitive performance encompasses several abilities including memory, language, reaction time, focus, mood and information processing. How much cognitive decline is considered normal? Exciting New Ingredients for Improving Cognition Enhance energy production in the brain with Pyrroloquinoline Quinone. Vivimind, a supplement containing homotaurine, improves memory, learning ability and slows cognitive decline.

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Ayurveda and Cognition Bacopa and curcumin enhance cognitive health and have extensive research to support their efficacy. A new and highly bioavailable form of curcumin has gained worldwide attention.

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New Perspectives and Natural Compounds for Traumatic Brain Injury Learn about new insights into the pathophysiology behind traumatic brain injuries (TBI) and how to help heal them with natural substances.

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Common Supplements to Improve Memory and Cognitive Function Explore natural options to help protect and improve cognitive function.

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Stress-Induced Cognitive Dysfunction The body maintains a delicate balance of hormonal and neurotransmitter activity in order for the brain to function well and produce a healthy emotional response.

Published in Canada by Advanced Orthomolecular Research Inc. Publisher/Editor-in-Chief Jaime Thomas, BSc Research & Writing Dr. Traj Nibber, PHD Dr. Colin OBrien, ND Dr. Chantal Ann Dumas, ND (Qc) Dr. Paul Hrkal, ND Adesh Nibber Graphic Design/Art Production Neil Bromley Alvin Cha email: graphics@aor.ca

Advances in Orthomolecular Research is published and distributed through integrative physicians, health care practitioners, and progressive health food retailers. The content of this magazine is provided for informational purposes only, and is not intended as medical advice for individuals, which can only be provided by a healthcare professional. Contents and design 2013 AOR. Any reproduction in whole or part and in print or electronic form without express permission is strictly forbidden. Permission to reproduce selected material may be granted by contacting the publisher.
Volume 4 Issue 4

Digital versions of this magazine and back issues are available online at www.AOR.ca

ADVANCED
ORTHOMOLECULAR RESEARCH

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Memory and Cognitive Performance

The human brain is like no other in terms of its ability to simultaneously synthesize information and carry out complex tasks on a regular basis. While it would be naive to say that we fully understand its interrelationship with the rest of the body and our environment, modern research has made great strides to elucidate its various structures and functions. Here is a brief look at our current understanding of cognitive function and the risk factors that threaten its well-being. While a focus on memory is highlighted, all aspects of cognitive performance including language, reaction time, focus, mood and information processing must be assessed together, due to the minds highly integrative nature. What is Normal? It is widely accepted that memory and other cognitive functions decline with age, but how do we know if someone has a normal amount of decline? A literature review published in 2004, concluded that no cognitive decline is normally seen before the age of 60.1 Yet, there are many that question this statement and contend that signs of deterioration can be seen at an even earlier age. Challenging this school of thought, a more recent study in 2012 showed that cognitive decline might normally be seen as early as age 45!2 Before going any further, it is important to note that not all of our cognitive abilities peak at the same age. The ability to process information in a rapid manner peaks around the relatively young age of 25.1 In other words, after age 25, the rate at which people understand and utilize new information generally starts to slow down. In contrast, verbal memory, inductive reasoning and spatial reasoning all peak around the age of 53. Finally, verbal abilities actually peak after age 60!1 Considering all of these facts, it is not fair to simply say that ageing leads to cognitive decline. Researchers have also shown that not all cognitive functions wane in the same manner or to the same degree. For example, it is now well known that the ability to encode new memories and process information at a rapid pace both steadily decline with age.1 Working memory also steadily declines; that is, the skill of utilizing short-term memory to manipulate and use relevant information. However, it is interesting that shortterm memory on its own does not show this downhill pattern throughout life. Short-term memory is found to have

very slight declines throughout adult life until finally hitting a turning point somewhere after the age of 70, where it starts a sharper decline.1 Similarly, autobiographical memory, semantic knowledge, emotional processes and vocabulary remain fairly stable until a dip late in life.1 Of course, there are variations among individuals for all of these abilities, but the general trends remain the same. Cognitive deterioration can also tell us a lot about our overall health. Interestingly enough, an acceleration of cognitive decline is often seen 3-6 years before an individuals death.3,4 In a sense, cognitive function is a relative measurement to ones own baseline status and can be a strong predictor of mortality if interventions are not applied. Overall, its important to know that there is a wide range of cognitive decline, some of which may be considered normal and others that may require medical attention. See Key Terms for a brief understanding of the various levels of cognitive deterioration and memory loss. Measuring Cognitive Decline: The Mini-Mental State Exam (MMSE) In order to provide a solution to any problem, it is first imperative to understand the problem and its severity. If you misplace your wallet and you are unable to remember its location, does it mean that youre a candidate for dementia? Of course notif it only happens once or twice. But if youre having difficulty, on a daily basis, with simple tasks like remembering the location of basic items, bathing, handling finances, or maintaining hobbies then it may be of concern. Dementia is a set of signs and symptoms in which brain function, such as memory, language, problem solving and attention are affected. Alzheimers Disease is just one of several different forms of dementia. So how can we determine if an individual is simply ageing in a healthy manner or if they are on their way toward Alzheimers Disease (AD)? As much as we can rely on our family, friends or even physicians to notice changes in our mental health, an objective measure

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must be implemented in order to better determine what areas of cognitive function may be impaired and to what extent. With this in mind, many assessments are available to determine the global level of cognitive decline, but perhaps the most commonly used tool by practitioners is the Mini-Mental State Exam (MMSE).7 The MMSE contains 19 items designed to measure a variety of functions, and ultimately gives a score between 0-30 indicating whether a cognitive deficit or dementia may be present. Examples of typical questions used on the MMSE can be found on page 6. The cognitive functions that are measured include the following7: Orientation: knowing details about the current time and location Attention: the ability to, for example, spell a common word backwards Registration: measured by repeating named prompts (immediate memory) Recall: measures short-term verbal memory Language: the ability to write, speak and understand language Praxis: the ability to put thoughts and ideas into action The MMSE is a popular test because of its relatively simple design and implementation, along with its ability to measure cognitive change over time.7 It has also been shown to correlate quite well with the abilities of individuals to carry out functional everyday tasks, thereby giving a good indication of how cognitive decline may be affecting day-to-day living.8 For example, when a person exhibits that they are oriented and attentive through MMSE testing, these findings correlate well with the ability to communicate by telephone, recognize driving rules and road signs, balance a checkbook, and carry out shopping tasks from memory.8 On the other hand, the MMSE does have its limitations. It is considered unreliable for measuring subtle changes in ability and is perhaps more indicated for repeated use to determine over a longer period of time whether cognitive decline or improvement has occurred.7 There are well-known ceiling and

The Nun Study The Nun Study is one of the best examples of how healthy diet and lifestyle choices can preserve cognitive function in ageing individuals. The Nun Study involves the ongoing functional assessment of women at the Catholic Order School Sisters of Notre Dame, with additional permission to assess the brains of deceased sisters for autopsy. Findings have shown that the relative non-occurrence of Alzheimers Disease (AD) in the nuns correlate with their cognitive capacity, lifestyle, and diet. In other words, some combination of their unspoiled lifestyles (including diet, spirituality, community life, mental exercise, etc.) all seem to have contributed to a much lower incidence of AD than the general population. 5,11 Key Terms Age-Associated Memory Impairment (AAMI): not considered a pathological condition. While AAMI may be annoying for the individual, the memory loss is considered a part of normal ageing similar to fading eyesight.5 Mild Cognitive Impairment (MCI): cognitive deterioration that is measurable based on clinical assessments and noticeable by others. However, it is not severe enough to consistently impair daily productivity in other words, the efficiency of performing daily activities may be decreased but not so much that the tasks must be discontinued.5 Dementia: a group of disorders that cause cognitive decline as a result of death or damage to brain cells. Cognitive decline must be present in two of four essential cognitive functions (1. Memory; 2. Language/speech; 3. Visual processing; 4. Planning capacity/ability to carry out complex tasks).5 Alzheimers Disease (AD): a form of dementia carrying similar criteria. The main differentiating feature is the deposition of abnormal protein plaques in the central nervous system (known as beta-amyloid and neurofibrillary tangles).5 Note: there is significant overlap between these definitions and even researchers have found it difficult to definitively differentiate between these terms.6 These are given as general guidelines only in order to better understand the varying degrees of memory/cognitive decline. floor effects of the MMSE, meaning that it cannot detect cognitive changes in those individuals on extreme ends of the spectrum (for example in a 90-year old with severe dementia or a highly educated 40 year old).9 Nevertheless, the MMSE should be considered a great preliminary screening tool used in the assessment of cognitive decline. Depending on the circumstances, more specific and integrated testing may be necessary. Does Memory Loss Always Lead to Alzheimers Disease? As described in the Key Terms text box, age-associated memory impairment (AAMI) appears to be independent and unrelated to the progression of Alzheimers Disease (AD).5 However, there is no consensus as to whether AAMI bears an increased risk for AD. One researcher has concluded that there is zero additional risk but others claim a three-fold increased risk.5

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Examples of Mini-Mental State Exam Questions 1. What day of the week is it today? 2. Repeat these words: apple, penny and table. Try to remember them, as you will be asked to recall them at a later point in the exam. 3. Can you tell me the name of the city that were in? 4. Please spell the word world. Now, spell the same word backwards. 5. Can you perform this action?: CLOSE YOUR EYES. 6. List the three words that you were asked to try to remember. 7. Write a complete sentence anything that comes to mind (it should have a verb and a subject). *Please Note: These questions are only provided as examples. This is not a full MMSE, nor does it qualify for diagnosis or proper assessment of cognitive function. For a full examination, be sure to see your healthcare practitioner. Elevated homocysteine levels Hypertension Cardiovascular disease Impaired glucose tolerance (conditions such as prediabetes) and type 2 diabetes mellitus Obesity Dehydration Chronic alcohol abuse Skipping breakfast High stress and elevated cortisol levels Poor diet (specifically high intake of total fat, saturated fat and cholesterol) Multiple mineral and vitamin deficiencies

Medical Conditions

Lifestyle Factors

Table 1: Factors That Impair Cognitive Performance According to the most current evidence, it seems as though individuals with mild cognitive impairment (MCI) tend to progress toward dementia, yet not necessarily AD.5 In fact, certain studies have shown that up to 25 percent of those with MCI can actually revert to normal cognitive capacity.10 To add to the perplexity, a subgroup of MCI individuals with quite severe memory loss, termed amnestic MCI (aMCI), do conclusively show an increased risk for the development of AD. In patients with aMCI, more than half progress to AD.5 In this sense, severe memory impairment in combination with other cognitive deficits does warrant more investigation and treatment interventions to, perhaps, decrease the likelihood of progression to AD. Much of the difficulty in determining an accurate risk assessment lies in the fact that there are many characteristics overlapping between the categories of cognitive function. For example, one study showed that 67% of individuals diagnosed with AAMI could also be identified as MCI subjects.6 For these 67%, their risk assessment varies quite a bit depending which category they are placed in. The reason for this variation, of course, comes down to differences in subjective measures and differences between objective tests (such as using the MMSE versus utilizing another cognitive test).6 Given the complexity of categorizing cognitive deficit, as well as the multiple and interconnecting risk factors associated with decline, it appears prudent to take a multi-factorial approach to mitigate and offset any

risk factors that may be present for the development of MCI, AD or any form of dementia.5,11 Essentially, given that there may be an increased risk for dementia and AD with any memory loss, isnt it worth taking all possible measures to offset this risk, just in case? Preserving Memory and Cognitive Function A list of factors that appear to impair cognitive performance including memory function,12-21 can be seen in Table 1. If you look closely at this list of risk factors, you will see that many, if not all, are caused by poor lifestyle and dietary health. It is clear that nutrition and lifestyle improvements must be primary interventions for the prevention of memory and cognitive impairments. A diet high in polyunsaturated fats (such as those found in fish), monounsaturated fats (such as those found in olive oil), vitamin E, polyphenols and antioxidants (in foods such as citrus fruits and vegetables) has been shown to possibly slow down the rate of cognitive decline and prevent progression to AD.1 Unfortunately, with the many challenges facing optimal nutrition, supplemental nutrients are often indicated as well. Certain supplements have been proven as effective treatments for cognitive decline and should be considered adjunctive measures with dietary and lifestyle improvements (see articles Supplements Known to Improve Memory and Ayurveda and Cognition). Aside from mitigating risk factors through dietary measures, perhaps the most important preventative measure and disease intervention is mental exercise. Research has shown that the old adage, Use it or lose it, holds true in the context of cognitive health.1,5 Animal studies have shown that mental exercise increases neurogenesis (growth of the nervous system), while clinical observations support this idea that the human brain is capable of rebuilding failed circuits.5 A randomized control trial performed in 2006 showed that a cognitive training program for 10 weeks led to significant

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cognitive improvement over those individuals that did not participate in the training program.22 This positive effect was seen 5 years after the training was performed! It should be noted that a random sample of the treatment group received additional training sessions at 11 and 35 months that led to even better outcomes.22 Intuitively, this means that the more often we are exercising our brains, the better they function over time. Physical exercise has also shown promise in the prevention and treatment of cognitive deterioration. Certain studies have found that physical exercise

aids executive function and overall cognitive function, while also reducing the amount of brain density loss with age (specifically in areas used for executive processes).1 On the contrary, a review released in 2011 stated that although there are numerous positive studies supporting the notion that exercise reduces the risk of cognitive decline, there is insufficient evidence to fully prove this.23 At the very least, we know that exercise decreases the risk of developing other chronic diseases and therefore may be viewed as a primary intervention for reducing the risk of cognitive deterioration. References

As with all traits, there is a natural variation among the population in terms of cognitive function. Not everyone has the same ability to store, process and utilize information, but this does not mean that everyone cannot maximize the potential that they do have. A mixture of lifestyle, environmental, dietary and genetic factors all play a part in the maintenance, or deterioration, of our cognitive health. Without a doubt, healthy dietary habits, consistent mental exercise and the prevention of chronic disease must be the primary treatment for the preservation of cognitive function.

1. Hedden T and Gabrieli JDE. Insights in the ageing mind: a view from cognitive neuroscience. Nature Reviews (Neuroscience) 2004; 5: 87-97 2. Singh-Manoux A, Kivimaki M, Glymour M, et al. Timing of onset of cognitive decline: results from Whitehall II prospective cohort study. BMJ 2012;344:d7622 doi: 10.1136/bmj.d7622 3. Small BJ, Fratiglioni L, von Strauss E, et al. Terminal decline and cognitive performance in very old age: does cause of death matter? Psychol. Aging 2003; 18:193202 4. Wilson RS, Beckett LA, Bienias JL, et al. Terminal decline in cognitive function. Neurology 2003; 60:17821787 5. Kidd, Parris M. Alzheimers disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Alt Med Review 2008; 13(2): 85-115 6. Bartrs-Faz D, Junqu C, Lpez-Alomar A, et al. Neuropsychological and Genetic Differences Between Age-Associated Memory Impairment and Mild Cognitive Impairment Entities. Journal of the American Geriatrics Society 2001; 49:985-990 7. Marioni RE, Chatfield M, Brayne C, et al. The Reliability of assigning individuals to cognitive states using the mini mental-state examination: a population-based prospective cohort study. BMC Medical Research Methodology 2011; 11:127-132 8. Razani J, Wong JT, Dafaeeboini N, et al. Predicting everyday functional abilities of dementia with the mini mental state examination. J Geriatr Psychiatry Neurol 2009; 22(1):62-70 9. Tombaugh TN and McIntyre NJ: The mini-mental state examination: a comprehensive review. J Am Geriatr Soc 1992, 40(9):922-935. 10. Rosenberg PB, Johnston D, Lyketsos CG. A clinical approach to mild cognitive impairment. Am J Psychiatry 2006;163:1884-1890. 11. Tyas SL, Snowdon DA, Desrosiers MF, et al. Healthy ageing in the Nun Study: definition and neuropathologic Correlates. Age Ageing. 2007 November ; 36(6): 650655. 12. Grandjean AC and Grandjean NR. Dehydration and cognitive performance. J Am Coll Nutr. 2007; 26(5):549S-554S. 13. Adan A. Cognitive performance and dehydration. J Am Coll Nutr. 2012; 31(2):71-8. 14. Ceballos NA. Tobacco use, alcohol dependence, and cognitive performance. J Gen Psychol. 2006; 133(4):375-88. 15. Teunissen CE, van Boxtel MP, Jolles J, et al. Homocysteine in relation to cognitive performance in pathological and non-pathological conditions. Clin Chem Lab Med. 2005; 43(10):1089-95. 16. Greenwood CE. Dietary carbohydrate, glucose regulation, and cognitive performance in elderly persons. Nutr Rev. 2003; 61(5-2):S68-74. 17. Grima NA, Pase MP, Macpherson H, et al. The effects of multivitamins on cognitive performance: a systematic review and meta-analysis. J Alzheimers Dis. 2012;29(3):561-9. 18. Crichton GE, Elias MF, Buckley JD, et al. Metabolic syndrome, cognitive performance, and dementia. J Alzheimers Dis. 2012; 30(S2):S77-87. 19. Hoyland A, Dye L, Lawton CL. A systematic review of the effect of breakfast on the cognitive performance of children and adolescents. Nutr Res Rev. 2009; 22(2):220-43. 20. Eilander A, Gera T, Sachdev HS, et al. Multiple micronutrient supplementation for improving cognitive performance in children: systematic review of randomized controlled trials. Am J Clin Nutr. 2010; 91(1):115-30. 21. Leininger S and Skeel R. Cortisol and self-report measures of anxiety as predictors of neuropsychological performance. Arch Clin Neuropsychol. 2012 May;27(3):318-28 22. Willis SL, Tennstedt SL, Marsiske M, et al. Long-term effects of cognitive training on everyday functional outcomes in older adults. JAMA 2006; 296(23):2805-14. 23. Snowden M, Steinman L, Mochan K, et al. Effect of exercise on cognitive performance in community-dwelling older adults: review of intervention trials and recommendations for public health practice and research. J Am Geriatr Soc. 2011 Apr;59(4):704-16

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Exciting New Ingredients for Improving Cognition

Pyrroloquinoline Quinone (PQQ) PQQ is a relatively large molecule that was first discovered in bacteria, by scientists in 1979. The significance of this molecule wasnt fully realized until a few years later when researchers found that the PQQ molecule could take part in redox reactions. These reactions are vital to the body for energy generation. Energy is the key, since it is required in carrying out virtually all the functions in a cell including: growth, repair, reproduction, synthesis, breakdown, waste removal and others. If energy isnt produced rapidly and efficiently then cells die. How PQQ Functions in the Body PQQ research was taken up by the Japanese; the mechanism of action was painstakingly worked out and attributed to these redox reactions. Redox reactions are a two way street where both oxidation (gain of oxygen or loss of electrons) and reduction (loss of oxygen or gain of electrons) occur simultaneously. In other words, while one molecule is being oxidized, the second is being reduced. Redox reactions allow cells to do two things at once, while saving considerable amounts of energy rather than performing these reactions separately. Redox reactions are an essential part of cells existence, and tens of thousands of these reactions occur at any one time. In this regard, PQQ is detected in various tissues and in bodily fluids such as saliva and tears and breast milk. PQQ acts as a catalyst by speeding up reactions, thus saving cells even more energy. Some researchers have classified this as a co-enzyme and a vital ingredient for cell survival, and thus have pushed for PQQ to be classified as a B vitamin; the jury is still out on the latter request. Nonetheless, researchers and clinicians have come to realize and appreciate the importance of PQQ in various diseases but especially in cognitive health. PQQs Role in Cognitive Health Researchers realized early on that people who consumed quantities of foods rich in PQQ such as tofu, celery, bell peppers and various fermented foods, had better brain function than people consuming lower quantities. This led scientists to look at the effect of PQQ on memory, learning, and other related cognitive functions. At first

they looked at PQQs mode of action in animals and then in humans. The Research on PQQ Animal studies have shown that PQQ protects nerve cells from damage caused by various toxins, it prevents oxidation of nerve tissue by quenching free radicals that otherwise cause much destruction, it increases the production of nerve growth factor which protects nerve cells and was shown to improve the memory tasks that the animals performed. In addition, it was discovered that PQQs effectiveness was enhanced when used in combination with another important molecule called Coenzyme Q10. Recently, two human studies have looked at the PQQ+CoQ10 combination and the effects on memory. The first study of 12 weeks duration and which was a double-blind placebo controlled randomised study in healthy patients, looked at three different supplement groups: (i) 22 patients received 20mg of PQQ, (ii) 24 patients received 20mg of PQQ plus 300mg CoQ10 and, (iii) 23 patients received a placebo. Patients performed various verbal and identification memory tests for the study. Both the PQQ and PQQ+CoQ10 groups performed much better than the placebo group in terms of improved memory scores. However, the PQQ+CoQ10 group was even better than the PQQ group on its own; thus indicating the synergy between the two molecules. A second study published in 2012 showed that when 20mg of PQQ alone was administered for 8 weeks, it significantly improved sleep quality and duration, reduced anxiety and fatigue, and improved overall quality of life. PQQ+CoQ10 presents a novel and a safe approach to maintaining healthy brain function in terms of memory and learning. Vivimind In the pharmaceutical world, all drugs have to go through extensive testing and studies from preclinical (test tube and animal), phase I (usually to determine pharmacokinetic profile,

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absorption, distribution of the drug in various tissues, and its excretion), Phase II (which determines the safety and establishes the dose required), and finally phase III which is the last, most expensive part, and involves hundreds to thousands of patients to determine a clinical end point (such as a reduction in pain or inflammation or an improvement of memory or any other positive/negative outcome). It is rare to find a natural health product that has a completed phase III study. The costs are just too high. At best, most natural health products stop at phase I and the odd one proceeds to a phase II study. Vivimind is one of the very few natural health products that has successfully completed all the phases that are normally required for a drug approval, and has thus generated unprecedented safety and efficacy data unlike any other natural health product.

Researchers at Queens University in Kingston, Ontario discovered a unique molecule that was found in certain seaweeds and which had remarkable properties in improving memory, learning, and slowed the normal aging process of the brain. The molecule was identified as homotaurine, a close relative of the amino acid taurine, but with unique and distinctive properties that taurine does not possess. A Canadian drug discovery company decided to test this molecule and conduct all the studies required, from pre-clinical all the way to phase III studies. The company spent over two hundred million dollars and took fifteen years to conduct testing in over two thousand patients across sixtyseven centres in Canada, US and Europe to complete sixteen studies in total (see Table 1). Unfortunately, homotaurine just missed the relevant statistical significance value in conclusively

demonstrating the efficacy using the standard psychometric tests. Health Canada required additional studies to be conducted before any Alzheimers disease claim would be granted. The company decided to abandon the drug application as this would cost a lot more money and time. Subsequent analysis of the data however, showed a clear statistically significant evidence of effectiveness in several cognitive functions including: memory preservation, maintenance of verbal skills and execution of various tasks, all of which are severely affected in Alzheimers disease (see Figure 1). In addition, homotaurine demonstrated a highly significant effect in a high-risk group of Alzheimers disease patients, those carrying the ApoE4 gene (see Figure 2). Approximately, a quarter of the AD population carry this aggressive gene.

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The company decided to market homotaurine as a natural health product under the trade name Vivimind, for maintaining optimal cognitive health. Health Canada allowed the following claim for Vivimind, May help support the specific area of the brain known as the hippocampus. The hippocampus is the part of the brain that is responsible for learning and memory. As we age, this area of the brain starts to shrink due to a loss of brain tissue and nerve cells. This is a normal part of ageing, but in Alzheimers disease this process is greatly accelerated. Magnetic Resonance Imaging (MRI) of the brain shows that Vivimind greatly reduces the loss of brain tissues by an incredible

68% (see Figure 3) as compared with placebo group. What is the mechanism of action of Vivimind? Studies have shown that Vivimind acts via two distinct pathways: It reduces and helps clear the gluelike deposits of the highly toxic betaamyloid peptide that forms plaques in the brain. It inhibits the formation of the amyloid tendrils which can literally choke the nerve cells (see Figure 4) Not only does Vivimind reduce the formation of these toxic plaques and fibril-like projections, but Vivimind may also help clear any such deposits from the brain. One of the key requirements of References

any product that can help improve cognition and/or prevent accelerated ageing of the brain, is for that molecule to be able to get into the brain by bypassing the super fastidious gatekeeper known as the blood brain barrier. Vivimind actually gets into the brain easily and thus is able to perform its function. Finally, Vivimind does not interfere with important liver detoxification enzymes such as Cytochrome P450, or even interact with blood thinning drugs like warfarin, unlike supplements such as Ginkgo biloba and vitamin E. Vivimind has extensive data showing both safety and effectiveness in improving various cognitive parameters (see Table 2 on page 9).

1. Aisen PS, Gauthier S, Ferris S et al Tramiprosate in mild-to-moderate Alzheimers disease- a randomised, double blind, placebo-controlled, multi-centre study Arch Med Sci. 2011; 1: 102-111 2. Caltagirone C, Ferrannini L, Marchionni N et al The potential protective effect of Tramiprosate (homotaurine) against Alzheimer disease: a review Aging Clin. Exp. Res. Sept 5 2012 3. Greenberg S M, Rosand J, Schneider AT et al A phase 2 study of tramiprosate for cerebral amyloid angiopathy Alzheimer Dis. Assoc. Discord. 2006; 20: 269-274 4. Koikeda T, NereNo M, and Masuda K et al Pyrroloquinoline quinone disodium salt improves higher brain function. Med Consult New Remedies, 2011; 48: 519-527 5. Nakano M, Yamamoto T, Okamura H et al Effect of pyrroloquinoline quinone(PQQ) on mental status of middle-aged and elderly persons. FOOD style, 2008; 21 13: 50-53 (Japanese) 6. Nakano M, Takeda H, Yamazaki M et-al Effects of oral supplementation with pyrroloquinoline quinone on stress, fatigue, and sleep. Functional foods in health and disease, 2012; 2: 307-324 7. Ohwada K, Takeda H, Yamazaki M et al Pyrroloquinoline quinone(PQQ) prevents cognitive deficit caused by oxidative stress in rats. J Clin Biochem Nutri, 2008; 42: 29-34. 8. Saumier D, Duong A, Haine D et al Domain-specific cognitive effects of tramiprosate in patients with mild to moderate Alzheimers disease: ADSS-cog subscale results from the Alphase study J Nutr Health Aging, 2009; 13: 808-812 9. Zhang Y, Feustel PJ, Kimelberg HK et al Neuroprotection by pyrroloquinoline quinone (PQQ) in reversible middle cerebral artery occlusion in the adult rat. Brain Res, 2009; 1094: 200-206.

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Common Supplements to Improve Memory and Cognitive Function

Acteyl-L-Carnitine Acetyl-L-Carnitine (ALC) is the ester form of the amino acid, L-carnitine, and also the form capable of passing the blood-brain barrier to enter the central nervous system.1 It is quite a versatile nutrient as it acts on many different metabolic pathways within the body. Specifically, ALC helps to transport acetyl Coenzyme A into the cell mitochondria, a process necessary for fatty acid oxidation and cellular energy production within the Krebs cycle.1 It also stimulates protein and membrane phospholipid synthesis. Lastly, ALC enhances acetylcholine production, a neurotransmitter primarily used in muscle activation but also other nervous system functions such as memory.2 Through these many pathways, ALC has been found useful in the treatment of Alzheimers Disease (AD) and other dementias. A recent 2012 study in Russia showed 3 grams of ALC to be safe and effective in the treatment of mild dementia caused by AD and vascular dementia (VD). This doubleblind, placebo-controlled trial of 12week duration, showed a 2.8 magnitude increase in cognitive function compared to placebo-treated patients, as determined by neuropsychological tests and cognitive assessment scales (such as the Mini-Mental State Exam [MMSE] see page 6 for details).3 It should be noted that the improvements in mild dementia were greater in those caused by AD as opposed to VD.3 A 2003 meta-analysis examined mild cognitive impairment or mild AD in a group of 21 ALC treated persons versus placebo groups. The study showed positive clinical and psychometric assessment scale results for ALC. In the majority of trials, 1.52 grams per day of ALC were studied and improvements were found as early as three months after supplementation began.4 One study specifically showed improvements in short-term memory, related tasks, and reaction time.5 Another study exhibited ALCs ability to improve long-term memory performance after one full year of

supplementation.6 Clearly, ALC has demonstrated a wide-range of applications on various markers of AD and cognitive impairment. ALC as a nutrient for preserving memory and cognition has also been studied in cases of hepatic encephalopathy (HE). HE is a common but serious complication in patients with liver cirrhosis that is accompanied by memory impairment, alterations in personality, poor concentration and impaired reaction times.7 A doubleblind, placebo-controlled trial found that 2 grams of ALC, twice daily over 3 months, resulted in significant improvements in short-term memory and overall neuropsychological function.7 It seems that ALC is capable of enhancing brain function under many causative circumstances! Animal studies have supported these findings by showing that ALC increases synaptic neurotransmission in the hippocampus of the brain.8 In other words, ALC helps brain cells communicate more efficiently in the area responsible for memory and learning! Part of the mechanism responsible for this improvement was confirmed to be increased acetylcholine synthesis and nerve cell activation by this key neurotransmitter.8 These findings were supported by the direct observation that the rats exhibiting increased synaptic neurotransmission also showed improved learning capacity.8 As an added benefit to ALCs use in memory and cognitive disorders, recent research in rat models has shown that ALC can be neuroprotective in cases of traumatic brain injury (TBI)9(See page 18 for more information on TBI). Lastly, ALC has also been shown useful in treating depression in the elderly, peripheral nerve disorders, HIV infection, attention deficithyperactivity disorder, cardiovascular complications and male infertility.1 Ultimately, these applications confirm its ability to generally improve the health of the nervous system, mitochondria and overall cellular function.1

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Phosphatidylserine Phosphatidylserine (PS) is one of the major phospholipids found in the brain.10 Among other phospholipids, it is structurally responsible for making up the cell membrane and functionally responsible for triggering cell-to-cell communication by transfer of biochemical information into the cell.10 Overall, PS plays a crucial role in cellular function and the overall function of the central nervous system! Animal research has suggested that PS supports the growth of the brain by increasing the density of nerve growth factor receptors, normally found to decrease as we age.10 PS has also shown to positively affect specific neurotransmitters in the brain including: acetylcholine, norepinephrine, serotonin and dopamine.11 With these mechanisms in mind, it comes as no surprise that PS has shown positive clinical research in its application for improved cognitive function. In fact, more than a dozen studies have exhibited significant improvements in learning, memory, concentration, and recall.12 In one of the largest studies examining the possible role in treating Age-Associated Memory Impairment (AAMI), significant improvements were recorded. 494 elderly patients

(aged 65-93) with moderate to severe cognitive decline (as measured by validated assessment tools, including the MMSE) were shown to benefit in areas of behavioral and cognitive performance with 300 mg per day of PS.13 The placebo group did not exhibit the benefits in learning and memory that the PS treatment group did after 6 months.13 A double-blinded, placebocontrolled trial utilizing 300 mg per day of PS also showed significant enhancements in memory tests with AAMI after only three weeks of treatment.14 Specifically, improvements were seen in the treatment subjects abilities to remember names and faces, recall telephone numbers and remember the placement location of keys and glasses. After three months, PS improved memory by 30 percent compared to placebo.14 It should be noted that the greatest improvements in test scores were shown in those with the lowest cognitive function at baseline. In these individuals, three months of PS supplementation led to an average cognitive age score of 52 in those with an original average score of 64.14 As one would expect, PS has also shown promise in treating AD. Significant improvements in global cognitive function have been shown

across the board, including activities of daily living, personal and nonpersonal memory, learning, motivation, socialization and information processing.15, 16, 17 Certain studies have shown that the greatest improvements are found in those AD patients with less severe cognitive decline.15, 16, 17 The most effective method of supplementation is oral ingestion, as PS readily passes through the blood-brain barrier, a trait necessary for therapeutic effects on the nervous system.10 Also, there has been some controversy over the source of PS and the corresponding effectiveness of supplementation. PS can be sourced from either bovine cortex (BC-PS) or soybean (SB-PS) and some research has questioned the effectiveness of the vegetarian source.18 However, a recent study confirmed that SB-PS is effective for memory and cognition, while also avoiding the theoretical risk for bovine spongiform encephalopathy from BS-PS and maintaining a sustainable source of PS.18 As a final note, PS has proven to also be beneficial for cognitive measures in cases of depression, ADHD and chronic stress 10, 19 and has demonstrated an extremely high safety profile.20 Most clinical studies examining the effects of PS on cognition and memory have dosed the nutrient at 200-400mg per day. Therefore, given current evidence, 300mg per day appears to be the best dosage for supporting memory related conditions.10 Citicoline Citicoline is a known neuroprotective agent and an extremely important molecule necessary for the biosynthesis of phosphatidylcholine, a cell membrane phospholipid in the nervous system.21 Levels of this crucial phospholipid can be depleted when the body needs to make more neurotransmitters (specifically acetylcholine), therefore compromising the integrity of the nerve cell membrane and overall nervous system.21 The good news is that citicoline can be taken as an oral supplement with fantastic bioavailability (almost all of the citicoline gets absorbed

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AOR Cognitive Health Products Dosage Recommendations According to Research Studies Mechanism of Action Acetyl-L-Carnitine (amino acid) 2-4g/day Phosphatidylserine (phospholipid) 300mg/day Citicoline (phospholipid) 1000mg/day

Supports protein synthesis Increases density of nerve growth receptors Supports cell membrane and phospholipid synthesis Increases synaptic neurotransmission Neuroprotective agent Supports neurotransmitter function Enhances memory and provides support for cognitive disorders
into the bloodstream and passes the blood-brain barrier).21 Like PS, citicoline improves the structure and functionality of nervous system cell membranes, yielding improvements in memory and other cognitive measures. Specifically, much of the clinical research on citicoline has been applied to stroke victims. Phosphatidylcholine synthesis appears to be impaired after brain ischemia,22 indicating that supplementation of citicoline may be necessary to drive this pathway. After suffering a stroke, patients are at twice the risk for developing dementia and can often be left with deficits in cognitive abilities.23 With this in mind, preventative measures to reduce this risk are extremely valuable. Alvarez-Sabin et al. found that 1000mg per day improved cognitive function at 6 and 12 months poststroke (specifically in areas of attention, executive function and temporal orientation).23 Another analysis stated that initiating citicoline within 24 hours after the occurrence of a stroke increases the probability of complete recovery at three months.24 Most recently, researchers in Italy examined the effects of citicoline in those with mild vascular cognitive impairment and no diagnosis of AD. After 9 months of taking 500mg per day, the treatment group (mean age of 79) did not show deterioration in mental function based on MMSE scores, whereas the control group showed significant declines.25 These findings are quite significant because much of the research examining citicoline has not looked at its effects for such a long duration of time. Researchers in the Italian study concluded that the most pronounced benefits of citicoline on vascular cognitive impairment might be seen over an even greater duration of use.25 Citicoline has also shown application as a memory aid without vascular causes, most likely through the enhancement of neurotransmitter synthesis in these circumstances. Animal studies in aging rats and young dogs have clearly shown its usefulness in enhancing memory and learning,26, 27, 28 while human clinical trials have supported these findings. A double-blind, randomized control trial found that 1000-2000mg of citicoline for up to 5 months duration led to improved verbal memory in individuals with poorer-than-average memory.29 This study built on the previous research showing that taking 1 gram per day of citicoline for 6 weeks enhanced global memory and, specifically, acquisition efficiency (the ability to acquire new memories) in those with mild-to-moderate memory loss.21 Finally, citicoline has also shown promising application in treating other conditions including Parkinsons (due to its dopaminergic action),21 amnestic mild cognitive impairment,30 earlyonset AD,31,32 spinal cord or brain injury33 and glaucoma.21 Please see the article titled Traumatic Brain Injury for more information on citicolines use in preserving cognitive function after physical trauma to the head. Overall, citicoline shows promise in treating memory deficits and cognitive decline due to a variety of causative factors, and also through a variety of mechanisms. A 2005 Cochrane Review looked at all of the data from published, double-blind, randomized human trials on citicoline and cognitive impairment at the time. It concluded that there was clear evidence of the benefits of citicoline on memory function and behavior.34 It is clear that anyone looking to support their brain and nervous system function should consider the benefits of citicoline supplementation quite seriously.

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References
1. Acetyl-L-Carnitine Monograph. Alternative Medicine Review 2010; 15(1):76-83 2. Michael E Hasselmo. The role of acetylcholine in learning and memory. Curr Opin Neurobiol. 2006 December; 16(6): 710715. 3. Gavrilova SI, Kalyn IaB, Kolykhalov IV et al. Acetyl-L-carnitine (carnicetine) in the treatment of early stages of Alzheimers disease and vascular dementia. Zh Nevrol Psikhiatr Im S S Korsakova. 2011;111(9):16-22. 4. Montgomery SA, Thal LJ, Amreim R. Meta-analysis of double blind randomized controlled clinical trials of acteyl-l-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimers disease. Int Clin Psychopharmacol 2003; 18:61-71 5. Rai G, Wright G, Scott L, et al. Double-blind, placebo controlled study of acetyl-L-carnitine in patients with Alzheimers dementia. Curr Med Res Opin 1990; 11:638-647 6. Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-carnitine treatment in Alzheimers disease. Neurology. 1991; 41:1726-1732 7. Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl-L-Carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci 2008; 53:30183025 8. Kobayashi S, Iwamoto M, Kon K, et al. Acetyl-L-carnitine improves aged brain function. Geriatr Gerontol Int. 2010 Jul;10 Suppl 1:S99-106 9. Scafidi S, Racz J, Hazelton J, et al. Neuroprotection by acetyl-L-carnitine after traumatic injury to the immature rat brain. Dev Neurosci. 2010;32(5-6):480-7. 10. Phosphatidylserine Monograph. Alt Med Review 2008; 13(3):245-247 11. Richter Y, Herzog Y, Cohen T, et al. The effect of phosphatidylserine-containing omega-3 fatty acids on memory abilities in subjects with subjective memory complaints: a pilot study. Clinical Interventions in Aging 2010; 5:313-316 12. Kidd PM. Phosphatidylserine; membrane nutrient for memory. A clinical and mechanistic assessment. Altern Med Rev 1996;1:70-84. 13. Cenacchi T, Bertoldin T, Farina C, et al. Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging (Milano) 1993;5:123-133 14. Crook TH, Tinklenberg J, Yesavage J, et al. Effects of phosphatidylserine in age-associated memory impairment. Neurology 1991;41:644-649 15. Crook T, Petrie W, Wells C, et al. Effects of phosphatidylserine in Alzheimers disease. Psychopharmacol Bull 1992;28:61-66. 16. Amaducci L. Phosphatidylserine in the treatment of Alzheimers disease: results of a multicenter study. Psychopharmacol Bull 1988;24:130-134. 17. Klinkhammer P, Szelies B, Heiss WD. Effect of phosphatidylserine on cerebral glucose metabolism in Alzheimers disease. Dementia 1990;1:197201. 18. Kato-Kataoka A, Sakai M, Ebina R, et al. Soybean Derived Phosphatidylserine Improves Memory Function of the Elderly Japanese Subjects with Memory Complaints. J. Clin. Biochem. Nutr. 2010; 47:246255 19. Baumeister J, Barthel T, Geiss KR, et al. Influence of phosphatidylserine on cognitive performance and cortical activity after induced stress. Nutritional Neuroscience. 2008; 11(3):103-110 20. Vakhapova V, Richter Y, Cohen T, et al. Safety of phosphatidylserine containing omega-3 fatty acids in non-demented elderly: a doubleblind placebo-controlled trial followed by an open-label extension. BMC Neurology 2011, 11:79-80 21. Citicoline Monograph. Alt Med Review 2008; 13(1):50-57 22. Adibhatla RM, Hatcher JF, Dempsey RJ. Cytidine-5-disphosphocholine affects CTP-phosphocholine cytidylyltransferase and lysophosphatidylcholine after transient brain ischemia. J Neurosci Res 2004;76:390-396 23. Alvarez-Sabn J, Ortega G, Jacas C, et al. Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovasc Dis. 2013;35(2):146-54. 24. Davalos A, Castillo J, Alvarez-Sabin J, et al. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke 2002;33:2850-2857. 25. Cotroneo AM, Catsagna A, Putignano S, et al. Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clinical Investigation in Aging 2013; 8:131-137 26. Bruhwyler J, Liegeois JF, Geczy J. Facilitatory effects of chronically administered citicoline on learning and memory processes in the dog. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:115-128. 27. Drago F, Mauceri F, Nardo L, et al. Effects of cytidine-diphosphocholine on acetylcholine-mediated behaviors in the rat. Brain Res Bull 1993;31:485-489. 28. Petkov VD, Kehayov RA, Mosharrof AH, et al. Effects of cytidine diphosphate choline on rats with memory deficits. Arzneimittelforschung 1993;43:822- 828. 29. Spiers PA, Myers M, Hochanadel GS, et al. Citicoline improves verbal memory in aging. Arch Neurol 1996; 53:441-448 30. Gavrilova SI, Fedorova IaB, Gantman, Kalyn IaB et al. [Ceraxon (citicoline) in the treatment of the mild cognitive impairment syndrome]. [Article in Russian] Zh Nevrol Psikhiatr Im S S Korsakova. 2011;111 (12):16-20. 31. Caamano J and Gomez MJ. Effects of CDP-choline on cognition and cerebral hemodynamics in patients with Alzheimers disease. Methods Find Exp Clin Pharmacol 1994;16:211-218. 32. Alvarez XA, Sampedro C, Lozano R, et al.Citicoline protects hippocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypoperfusion in rats. Methods Find Exp Clin Pharmacol 1999;21:535-540. 33. Leon-Carrion J, Dominguez-Roldan JM, Murillo-Cabezas F, et al. The role of citicoline in neuropsychological training after traumatic brain injury. NeuroRehabilitation 2000;14:33-40 34. Fioravanti M and Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD000269

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Ayurveda and Cognition

Ayurveda or the science of life, is a widely popular system of healing and is considered the oldest as described in ancient Indian texts dating back to 3500 BCE. Classically, Ayurveda is a holistic method of treating health by addressing the physical, mental and spiritual aspects in unison. Diet, exercise and meditation play a key role in this traditional but highly effective system. Naturally, Ayurveda uses a wide variety of herbs and minerals in various combinations that still continue to be used today and that have been described in detail in numerous texts. Ayurveda and homeopathy are considered on par with the western based pharmacological medical system and are recognised by the government of India as legitimate medical systems. This brief review of Ayurveda and cognition will not cover the timehonored principles of Ayurveda, rather it will focus on the experimental and clinical evidence on the use of the herbs. There are many herbs that are highly regarded in Ayurvedic medicine including: Mucuna pruriens, Centella asiatica, Withania sominefera and many others. Unfortunately, many of the published studies reporting the use of such herbs are of poor quality in terms of design, quality, sample size, statistical analysis (or a lack of), not blinded and therefore allowing bias, and would not be accepted by many researchers as meaningful. However, two herbs that have good scientific data behind their use are turmeric and Bacopa. Epidemiologists, or scientists who study health in populations, often observe that the incidence of various neurological diseases in countries like India are often at the lower end of the spectrum. This indicates that lifestyle, diet, and the use of herbs and spices seem to be offering protection to the Indian population when compared to the western countries. India has some of the lowest rates of Alzheimers and Parkinsons diseases, other forms of dementia and depression. The regular use of various herbs and spices in the diet, such as turmeric in curries and Bacopa in tea, has been implicated in their protective effects. Bacopa Bacopa is an herb that grows throughout the Indian sub-continent and is so highly revered that it is called brahmi after one of the major Hindu deities, Bhrama the God of Creation. Bacopa is a popular and widely used herb throughout the whole of India, due to its remarkable and positive effects on cognition in persons of all ages. Typically the whole of the plant is used, especially the leaves and stem. There are various active components including alkaloids and saponins, but the main active compounds for cognitive effects are thought to be bacosides A and B.

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24 20 Plasma Curcumin (ng/mL) 16 12 8 4 0 0.0 1 2 3

95% Curcuminoids 95% Curcuminoids (650 mg dose (650 mggroup) dose group)

Figure 1. Mean plasma concentration of Longvida curcumin was 65 times more bioavailable than unformulated curcumin based on Cmax, and more than 100 times more bioavailable based on Area Under the Curve (AUC). One significant finding over the course of several bioavailability studies using different doses, is that Longvida curcumin dosages lead to therapeutic levels of free curcumin in the bloodstream and target tissues. Bacopa has been subject to extensive research in both animals and humans and produces a multitude of physiological effects. First, Bacopa is regarded as an important adaptogen. An adaptogen is any compound that helps the body maintain normal status-quo during any form of stress. Stress may be described as the sum total of all the reactions of the body that disturbs its normal equilibrium and homeostasis. In Ayurvedic texts, Bacopa is considered a tonic for both the brain and the body and this may reflect Bacopas ability to help the body cope with stress. As an example, animals given aspirin to cause stomach ulcers were largely protected when given Bacopa at the same time. Second, Bacopa has been used in patients to treat epilepsy, anxiety, insomnia, as well as for providing a mild analgesic effect. Perhaps the most important therapeutic effect of Bacopa is in the field of cognition. Bacopa has been studied for enhancing memory in children as well as in seniors. Behavioural animal studies confirm that Bacopa improves motor learning; in other words, animals seem to remember tasks better or are able to escape a maze much quicker than untreated animals. Other studies have shown that Bacopa protects against various toxins that act on the nerve cells as well as reversing amnesia induced by such toxins. Human Studies on Bacopa One human study involved children who were given Bacopa syrup. It was given to twenty children under the age of eight, while another group of children of same age were given syrup without any Bacopa in it. Improvements were noticed in word association, pattern recognition and other reasoning tests in the Bacopa group compared to the placebo group; these improvements were statistically significant. A second study in nineteen children diagnosed with attention deficit hyperactivity disorder (ADHD) was carried out for sixteen weeks. Like the previous study, positive results were noticed in various tests related to sentence repetition, memory, and other learning tasks. Researchers in Australia investigated the effects of Bacopa and tested the compound in eighteen normal healthy adults at a daily dose of 300mg. The study participants were evaluated two hours after intake with a battery of cognitive tests involving factors such as verbal recall of numbers, symbol recognition, speed of comprehension, reaction times and others. However, no difference was found in the Bacopa group when compared to the placebo group. Next, the researchers evaluated the same group after chronic use of Bacopa at a 300mg dose for twelve weeks; this time they found significant improvements in cognitive function. Other research groups in India have also found similar benefits for chronic use of Bacopa. Thus it seems that Bacopa works very well when taken on a regular basis. The mechanism of action of Bacopa seems to be that Bacopa increases levels of acetylcholine (Ach), an important chemical messenger in the brain. Lower levels of Ach have been linked to cognitive decline including Alzheimers disease. Bacopas ayurvedic reputation

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as a brain tonic for children and adults (especially seniors) has been confirmed by researchers. Curcumin The brightly coloured spice turmeric is a widely used condiment in South East Asia and beyond. Besides food application, the spice is used as a colouring agent, food preservative and for health benefits. Ayurveda lauds the diverse application of turmeric; its uses range from treating intestinal problems, fever, cataracts, inflammation and heart disease. It is also used as an antimicrobial, a topical treatment, to help prevent cancer, and of course for cognitive health. The active ingredients of the turmeric root are the three curcuminoids, of which by far the largest component is curcumin. Much of the research supports the use of curcumin in healthly brain function. Many research groups are actively looking at curcumins brain protective effects, especially against Alzheimers disease. One of the key requirements for any compound (natural or pharmaceutical) is the ability to cross

the blood-brain-barrier (BBB). The BBB offers a defence against unwanted entry to many compounds both friend and foe. The brain is after all the command centre and thus must be protected at all costs. The BBB acts as a gatekeeper, allowing access to key nutrients such as glucose and certain minerals, but also preventing access to others and therefore posing a challenge to the formulators of natural health products. Longvida- The Best Curcumin Supplement Available After studying the curcumin molecule for many years, scientists at the famed University of California at Los Angeles (UCLA) finally came up with a formulation that could get across the BBB and thus provide cognitive effects. They called this product Longvida (see www.longvida.com) and patented it. While a number of animal studies showed the positive effects of this molecule, the scientists wanted to see if the benefits could be translated to humans. Late last year, researchers led by Dr Di Silvestro at Ohio State University looked at 30 healthy adults and gave References

them the Longvida formulation. They found that not only did Longvida deliver high quantities of free curcumin due to its very high bioavailability, the highest in any formulation (see figure 1), but it also reduced the levels of one of the markers of Alzheimers disease called beta amyloid peptide. This small protein like structure is thought to be one of the culprits in the causation of this dreaded disease. Acting like Velcro, this glue-like protein sticks to the nerve cells causing their death. The fact that Longvida reduced its circulating levels was a significant finding. The Ohio State University Study is Important for the Following Reasons: A very low dose was used (only 80 mg which is the exact dose in AORs CurcuViva). The study was for only 30 days and it was remarkable that a significant effect was seen in such a short duration! The fact that significant results were seen in healthy adults may mean that in people with higher levels of this toxic peptide such as in Alzheimers patients, the results ought to be better.

1. Sharma R, Chaturvedi C, Tewari PV, et al. Bacopa monnieri in revitalizing intellectual functions in children. J Res Education. Indian Med, 1987 June 1-12. 2. Negi KS, Singh YD, Kushwaha KP, et al. Clinical evaluation of memory Plus in children with ADHD. Ind J Physciatry, 2000; 42: Suppl. 3. Bhattacharya SK and Ghosal S. Anxiolytic activity of a standardized extract of Bacopa monniera in an experimental study. Phytomedicine, 1998; 5: 77-82. 4. Nathan P J, Tanner S, Lloyd J, et al. Effects of a combined extract of Gingko biloba and Bacopa monniera on cognitive function in healthy humans. Human Psypharmacology Clin Exp, 2004;19: 91-96. 5. Stough C, Lloyd J, Clarke J, et al. The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Pshychopharmacology, 2001;156:481-484. 6. Nathan PJ, Clarke J, Lloyd J, et al. The acute effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy normal subjects. Human Psychopharmacology Clin. Exp. 2001; 16: 345-351. 7. Rai D, Bhatia G, Sen T, et al. Adaptogenic effect of Bacopa monniera (Brahmi). Pharmacolology, Biochemistry and Behaviour, 2003;75:823830. 8. Singh H K and Dhawan, B.N. Brain enhancing ingredients from ayurvedic medicine: quintessential example of Bacopa monniera, a narrative review. Nutrients, 2013;5:478-497. 9. Ma Q, Xiaohong Z, Fusheng Y, et al. Curcumin suppresses soluble tau dimers and corrects molecular chaperone, synaptic and behavioral deficits in aged human tau transgenic mice. J Biological Chemistry on line, published Dec 2012. 10. Disilvestro R, Joseph E, Zhao S, et al. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutrition Journal 2012, 11:79-87. 11. Gota V S, Maru GB, Soni TG, et al. Safety and Pharmacokinetics of a Solid Lipid Curcumin Particle Formulation in Osteosarcoma Patients and Healthy Volunteers. J. Agric. Food Chem. 2010, 58, 20952099 2095. 12. Begum A N, Hillman Z, Duran E, et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimers disease. Journal of Pharmacology and Experimental Therapeutics. 2008 Jul; 326:196-208.

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New Perspectives and Natural Compounds for Traumatic Brain Injury

Traumatic brain injuries (TBI) and concussions are generating greater medical and research interest as public awareness grows, especially in terms of their impact on younger and more vulnerable populations. A recent study found there are approximately 30,000 concussions or head related injuries reported annually among the 12 to 19 year old age group, with over 80% being sports related.1 While these numbers are increasing every year, the majority of concussions are still not being reported so the true numbers are most likely underestimated.1 An explosion of recent research has uncovered some of the pathophysiological pathways involved in TBI. While one unified theory has yet to be confirmed, there is emerging evidence that brain trauma causes neurotransmitter and calcium release which initiates a cascade of neuroinflammation, excitotoxin production, mitochondrial dysfunction and immune activation.2 People that sustain a TBI undergo a very brief period of increased metabolism as brain cells try to restore balance and deal with the trauma. Following the brief hypermetabolic period, brain tissue rapidly progresses into a hypometabolic state as mitochondria function is impaired. This state can last 7 days or longer (30 days in severe cases) depending on the severity of the TBI. A very prevalent problem is that many athletes underplay or hide their symptoms in order to return to activity earlier. The risk of a concussion appears to increase when the brain has suffered a prior concussive injury. Until recently, little has been known about the long-term effects of TBIs and sub-concussive injuries. The symptoms of most concussions (mild to moderate severity) resolve spontaneously after 1-2 weeks, but a small proportion (less than 10%) progress to more advanced stages with persistent symptoms and cognitive impairment.3 The spectrum of post-concussive conditions includes acute TBI symptoms, post-concussion syndrome (PCS), prolonged postconcussion syndrome (PPCS), mild cognitive impairment (MCI), chronic traumatic encephalopathy (CTE), and dementia pugilistica (DP).3 Incomplete recovery, early return to activity and multiple injuries may contribute to the

prolonged duration of symptoms and greatly increase the chance and severity of future concussions.3 TBI is a common form of injury, which often goes un-reported and is commonly mismanaged. Researchers are just now beginning to understand the complex pathophysiological cascade after a brain injury. The current treatment and management of TBI and PCS is rest, reduction of sensory inputs, and symptomatic treatment (for conditions such as depression).2 Conventional and pharmaceutical approaches have shown limited benefits due to their singular mechanisms. Currently, no neuroprotective treatment options exist that improve symptoms after a TBI.4 Now many researchers are starting to study a wide range of natural compounds and vitamins that have promising broadspectrum, neuroprotective and antiinflammatory activity. Natural Compounds for Neuroprotection and Recovery While the evidence is far from conclusive, some simple conclusions can be drawn and applied to clinical practice. Some of the most promising natural compounds in active treatment of TBI are CDP-choline, omega-3 fatty acids, curcumin, green tea extract, vitamin E and resveratrol. From a preventative perspective, a diet high in polyphenols found in colourful fruits and vegetables, and omega-3 fatty acids, along with supplementation of vitamin E, may improve recovery after a TBI. The one definitive point is that very few (if any) side effects and negative results have been found in trials with natural substances, making their use safe. We can remain cautiously optimistic that more evidence will emerge to support natural therapies for TBI. This article will explore a number of the most promising natural treatment options to address the symptoms and pathophysiological pathways found in TBI. CDP-choline and omega-3 fatty acids have the most evidence, while vitamin E, curcumin, green tea and resveratrol are some of the compounds which also offer potential therapeutic benefit in the treatment of TBI.

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CDP-Choline as a Beneficial Supplement for TBI Cytidine diphosphoryl choline (CDPcholine) was found to be beneficial in treating post-concussive symptoms. A double blind placebo-controlled study investigated the effects of CDP-choline on patients with a mild to moderate closed head injury (CHI) with treatment provided for a month following the injury. Fourteen young men admitted to the neurosurgery department after sustaining mild to moderate CHI were randomized to oral CDP-choline (1 g) and placebo control groups which were matched for age, education and severity of impaired consciousness. At baseline (prior to discharge) and at one month, examinations consisted of a structured post-concussive symptom interview and neuropsychological tests. Analysis of the neuropsychological findings revealed a significantly greater improvement in recognition memory for the CDP-choline treated patients, whereas other changes in test performance did not differ for the two groups.6 Although further study is warranted, these findings suggest that CDP-choline may be effective in treating mild to moderate CHI. Another single blind randomized study was conducted in 216 patients with severe or moderate head injury.7 The aim of the study was to compare the evolution of the injuries of those that received only conventional treatment with the evolution of those treated with CDP-choline. The results indicate that CDP-choline improves patient outcome. There was a trend towards a greater improvement in motor, cognitive and psychic alterations in the patients treated with CDP-choline, as well as a shortened hospital stay for the patients that initially presented with severe head injuries.7 Essential Fatty Acids Omega-3 polyunsaturated fatty acids have long been considered essential for brain development and function. Docosahexaenoic acid (DHA) (and to a lesser degree eicosapentaenoic acid (EPA)) is primarily found in nerve membranes and influences fluidity,

Causes of Brain Injury

Falls Motor Vehicle Falls Recreation Shaken Infant Syndrome Violence Motor Vehicle Violence Bicycles Motor Vehicle

Recreation Bicycles Motor Vehicle Violence Violence

Shaken Infant Syndrome

cell signaling, and inflammatory pathways.8 Since the human body cannot efficiently convert plant based essential fatty acids to EPA and DHA, fish oil supplements are the best source of these active components. It is important to note that while consuming fish that are high in omega-3 fatty acids is desirable, the high amount of heavy metals and polychlorinated biphenyls (PCBs) found in most fish is a concern, especially in regards to brain function.9 A number of trials in animal models of TBI have found that that DHA and omega-3 supplementation improves cognitive function, reduces neuronal edema, stabilizes cellular energy homeostasis and increases dendrite growth.10,11 One of these studies also showed that pre-injury dietary supplementation with fish oil also had a neuroprotective effect.10 Mechanistically and functionally, DHA and EPA have promising therapeutic value for neuroprotection, when consumed from plant and fish sources, or from high quality contaminant-free fish oil. Vitamin E One of the frequently studied natural compounds for brain health is vitamin E, a family of molecules that have a potent antioxidant effect in fatty tissue. A number of animal studies have found that vitamin E supplementation reduces lipid peroxidation and improves cognitive

performance following repetitive, concussive brain injury.12,13 Interestingly, supplementation before the concussions also had a neuroprotective effect.13 Unfortunately there have been conflicting studies on the benefits of vitamin E supplementation, calling into question its clinical application.14 Some of the conflicting results may be due to a number of flaws that exist in the use of vitamin E as an intervention in research trials. Vitamin E is a family of 8 molecules (four tocopherols and four tocotrienols) that function synergistically in human physiology. Most studies have used only low doses of alpha-tocopherol which has been shown to be the least active form of vitamin E and actually depletes the other forms.14 Gamma-tocopherol is the main anti-inflammatory component and has been found to be more effective than the alpha form in scavenging free radicals that cause inflammation.14 Emerging evidence suggests that the tocotrienol family provides even more benefits than the tocopherols in supporting brain and heart health.15 Curcumin While results are still preliminary, curcumin (from turmeric) extract is showing positive benefit in neurorecovery, membrane stabilization and reduction of oxidative stress in TBI models.16,17,18

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Metabolic disarray Lactate Cell swelling Brain oedema Excitotoxic effects Glutamate

Neuronal Death

Inflammation

Cytokines Chemokines Neurotrophins

Glutamine NMDA-receptor Axonal filaments Axonal cytoskeleton disruption Impaired axonal transport Axonal damage Reactive oxygen species Energy failure Nitric oxide species Oxidative stress

Microglia Leucocyte infiltration

Macrophages

Neuronal Death

Capillary Neutrophils Cell swelling and blood-brain barrier dysfunction Brain oedema ICP Ischemia

Figure 1. Pathophysiology of traumatic brain injury. (1) In traumatic brain injury, excitotoxic effects (which occur when nerve cells die from being over stimulated), are mediated by an increased concentration of extracellular glutamate resulting from neuronal death and overproduction. Normally glutamate is taken up by astrocytes (cells in the brain), which convert it into glutamine and deliver it back to neurons as an alternative energy source. If glutamate is excessively produced, the astrocytes cannot remove it from the extracellular space. (2) Glutamate binding to neuronal receptors, such as NMDA, causes the influx of Ca2+ and Na+ and the efflux of K+. This ion imbalance causes depolarisation of the cell membrane and an overload of intracellular Ca2+. (3a) Compromised mitochondrial integrity is followed by release of reactive oxygen species and nitric oxide species, which together cause the oxidative stress that damages membrane lipids, proteins, and DNA, eventually leading to death of the nerve cell. (3b) Free Ca2+ also activates several enzymes, such as caspases, which contribute to DNA fragmentation and cell apoptosis. Other calcium-activated enzymes such as calpains impair axonal transport and function. (4) Ischaemia (low oxygen) causes a shift to anaerobic metabolism by astrocytes, producing lactate, which provides an alternative energy source to neurons in a process called coupled lactate metabolism. (5) Neuroinflammation consists of activation of glial cells (line the exterior of the neuron), the astrocytes, and microglia, which undergo several morphological and molecular changes. Glial cells secrete inflammatory cytokines, chemokines (which stimulate the transmigration of activated blood leucocytes into the brain), and reparative factors such as neurotrophins. Together with fibroblasts, these cells form the glial scar, which impairs axonal regrowth. (6) Microglia accumulate in the injured brain region and phagocytose the debris that originate from dying cells. (7) Infiltrated neutrophils and monocytes sustain the immune response to injury, thus impairing the integrity of the bloodbrain barrier, which leads to increased extracellular fluid that, combined with cell swelling, leads to brain oedema and increased intracranial pressure. The impact of oxidative stress on neuronal function and plasticity after (TBI) is becoming increasingly recognized. Animal studies have evaluated the capacity of this powerful antioxidant found in curry spice and found it is able to counteract the oxidative damage encountered in the injured brain as well as interact with molecular mechanisms that maintain synaptic plasticity and cognition. Other animal data suggests that clinically achievable concentrations of curcumin reduce glial activation and

cerebral edema following neurotrauma. Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of Brain Derived Neurotrophic Factor, synapsin I, and cellular transcription factors that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. Further, another animal study revealed the potential of a curcumin derivative to promote membrane homeostasis following TBI, which may foster a new line of non-invasive therapeutic treatments for TBI patients by upregulation of molecules important for neural repair and plasticity. For more information on Curcumin, please see the article titled Ayurveda and Cognition. Green Tea, Resveratrol and Other Polyphenols EGCG-rich green tea extract has been shown to have antioxidant and anti-inflammatory effects in animal models of brain injury.19,20 There have also been a number of animal trials using polyphenols such as resveratrol, demonstrating anti-inflammatory and neuroprotective effects in TBI, but like green tea there have been no human trials to date.21,22 Endocrine Dysfunction and TBI There may be other factors to investigate in cases involving traumatic brain injuries. One study investigated the prevalence of anterior pituitary dysfunction in a multi-centre screening program across five German endocrine centres in patients rehabilitating from TBI. A total of 246 patients underwent a series of endocrine tests. In 21% of these TBI patients, some degree of impaired anterior pituitary function was observed. These findings strongly suggest that patients who suffer head trauma should routinely undergo endocrine evaluation and may benefit from supplements that help to balance the endocrine system such as adaptogenic botanicals and nutrients to support the adrenals, thyroid and other glands. Please see the article titled StressInduced Cognitive Dysfuntion: The Hormone-Neurotransmitter Connection for further information on the endocrine systems effects on cognitive health.

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References
1. Gordon KE, Dooley JM, Wood EP. Descriptive epidemiology of concussion. Pediatr Neurol. 2006 May;34(5):376-8. 2. Maroon JC, Lepere DB, Blaylock RL, et al. Postconcussion syndrome: a review of pathophysiology and potential nonpharmacological approaches to treatment. Phys Sportsmed. 2012 Nov;40(4):73-87. 3. Giza CC and Difiori JP. Pathophysiology of sports-related concussion: an update on basic science and translational research. Sports Health. 2011 Jan;3(1):46-51 4. McConeghy KW, Hatton J, Hughes L, et al. A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. CNS Drugs. 2012 Jul 1;26(7):613-36. 5. Blaylock R and Maroon J. Natural plant products and extracts that reduce immunoexcitotoxicity-associated neurodegeneration and promote repair within the central nervous system. Surg Neurol Int. 2012; 3: 19. 6. Levin HS.Treatment of postconcussional symptoms with CDP-choline. J Neurol Sci. 1991 Jul;103 Suppl:S39-42. 7. Calatayud Maldonado V, Calatayud Prez JB, Aso Escario J.J Neurol Sci. Effects of CDP-choline on the recovery of patients with head injury. 1991 Jul;103 Suppl:S15-8. 8. Dyall SC and Michael-Titus AT. Neurological benefits of omega-3 fatty acids. Neuromolecular Med. 2008; 10(4):219-35. 9. Mania, Wojciechowska-Mazurek M, Starska K, et al. Fish and seafood as a source of human exposure to methylmercury. Rocz Panstw Zakl Hig. 2012;63(3):257-64. 10. Mills JD, Bailes JE, Sedney CL, et al. Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model. J Neurosurg. 2011 Jan; 114(1):77-84. 11. Wu A, Ying Z, Gomez-Pinilla F. Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury. J Neurotrauma. 2007 Oct; 24(10):1587-95 12. Wu A, Zhe Y and Gomez-Pinilla F. Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats.Neurorehabil Neural Repair.2010;24:2908. 13. Conte V, Uryu K, Fujimoto S, et al. Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury. J Neurochem. 2004;90:75864. 14. Usoro OB and Mousa SA. Vitamin E forms in Alzheimers disease: A review of controversial and clinical experiences. Crit Rev Food Sci Nutr.2010;50:4149 15. Sen CK, Khanna S, Roy S. Tocotrienols: Vitamin E beyond tocopherols. Life Sci. 2006 Mar 27;78(18):2088-98. Epub 2006 Feb 3. 16. Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol. 2006 Feb;197(2):309-17. Epub 2005 Dec 20. 17. Laird MD, Sukumari-Ramesh S, Swift AE, et al. Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4? J Neurochem. 2010 May;113(3):637-48. 18. Sharma S, Ying Z, Gomez-Pinilla F. A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma.Exp Neurol. 2010 Nov;226(1):191-9. 19. Wei IH, Tu HC, Huang CC, et al. (-)-Epigallocatechin gallate attenuates NADPH-d/nNOS expression in motor neurons of rats following peripheral nerve injury BMC Neurosci. 2011 Jun 1; 12():52. 20. Itoh T, Imano M, Nishida S, et al. Neuroprotective effect of (-)-epigallocatechin-3-gallate in rats when administered pre- or post-traumatic brain injury. J Neural Transm. 2012 Nov 21. 21. Ates O, Cayli S, Altinoz E, et al. Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem. 2007 Jan; 294(12):137-44. 22. Gatson JW, Liu MM, Abdelfattah K, et al. Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury. J Trauma Acute Care Surg. 2013 Feb;74(2):470-4. Additional References Petraglia AL, Winkler EA, Bailes JE. Stuck at the bench: Potential natural neuroprotective compounds for concussion. Surg Neurol Int. 2011;2:146. doi: 10.4103/2152-7806.85987. Epub 2011 Oct 12 Bengmark S. Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases. JPEN J Parenter Enteral Nutr. 2006 Jan-Feb; 30(1):45-51. Baum L, Lam CW, Cheung SK, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008 Feb; 28(1):110-3. Wu A, Ying Z, Schubert D, et al. Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma. Neurorehabil Neural Repair. 2011 May;25(4):332-42. Park SK, Jung IC, Lee WK, et al. A combination of green tea extract and l-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study. J Med Food. 2011 Apr; 14(4):334-43. Begum AN, Jones MR, Lim GP, et al .Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimers disease. J Pharmacol Exp Ther. 2008 Jul; 326(1):196-208. DiSilvestro RA, Joseph E, Zhao S, et al. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutrition Journal 2012, 11:79 Petraglia AL, Winkler EA, Bailes JE. Stuck at the bench: Potential natural neuroprotective compounds for concussion. Surg Neurol Int. 2011;2:146. doi: 10.4103/2152-7806.85987. Epub 2011 Oct 12. Kakuda T. Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction. Pharmacol Res. 2011 Aug;64(2):162-8.

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Stress-Induced Cognitive Dysfunction: The HormoneNeurotransmitter Connection

Several studies have examined the influence of emotions on cognition, but common everyday situations also testify to the prevalence of this phenomenon. Indeed, who has never forgotten something important under the effect of acute stress, or hasnt witnessed a menopausal relative complaining about becoming forgetful? The mechanisms and neural circuits involved in emotions and cognition are inextricably linked, and the maintenance of this delicate neurochemical balance is easily disrupted from exposure to stress. Stress triggers a cascade of hormone and neurotransmitter release throughout the brain, affecting our thoughts, decision-making process and behavior. Understanding the Impact of Stress Hans Selye (1907-1982), a Hungarian endocrinologist who conducted his research in Montreal (Qubec), was

the first to give a scientific explanation for biological stress. Selye explained that in response to a stressor, the hypothalamic-pituitary-adrenal (HPA) system is activated, leading to a threestage bodily response.1 The HPA system triggers the production and release of steroid hormones (glucocorticoids), including cortisol. Cortisol is considered the primary stress hormone due to its importance in mobilizing systems throughout the body against a stressor. The HPA system also releases certain neurotransmitters (chemical messengers) called catecholamines, particularly dopamine, norepinephrine, and epinephrine. Catecholamines activate the amygdala, an area inside the brain which triggers an emotional response to the stressful event. The brain also releases neuropeptide S, a small protein that modulates stress by increasing alertness, decreasing sleep and generating a sense of urgency and anxiety in the individual facing the stressor. Effects of Stress on Cognitive Functions The prefrontal cortex (PFC) is the anterior part of the frontal lobes of the brain that governs higher-level cognitive processes and executive function. The basic activity of the PFC is considered to be orchestration of thoughts and actions in accordance with internal goals.2 Under optimal, stress-free conditions, microcircuits within the PFC work in concert to allow nuanced decisionmaking and inhibit inappropriate responses.3 During exposure to stress however, catecholamines (mainly norepinephrine and dopamine) and glucocorticoids (mainly cortisol) suppress activity in areas at the front of the brain concerned with short-term memory, concentration, inhibition, and rational thought. Glucocorticoids activate glucocorticoid receptors (GRs) in the hippocampus in order to store the emotionally loaded experience in long-term memory.4 Cortisol may also indirectly exacerbate working memory impairments through interactions with the catecholamine systems.5 This

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No Stress optimal

Stress-induced enhancement of D1 signalling

poor Low estrogen

D1 signaling

PFC function

High estrogen

Figure 1: Estrogen ahead of the curve hypothesis. Estrogens may amplify the stress response in females by raising baseline dopamine D1 signaling, thus making small shifts more apparent in behavioral measures. In this model, high and low estrogen females perform equally well at working memory tasks under no-stress conditions, but mild stress shifts high estrogen animals down into the far end of the D1 inverted U, while only pushing low-estrogens animals slightly across the middle. (adapted from Selye, H., 1976) sequence of mental events encountered during stress allows a person to react quickly in the face of a perceived danger, but it also interferes with the ability to handle difficult social or intellectual tasks and behaviors during that time. In primitive times, this brain action would have been essential for survival (long-lasting memories of dangerous stimuli would be critical for avoiding such threats in the future) but in todays world, the almost chronic activation of these same circuits by non-life-threatening stressors is proving detrimental to daily life. In addition to the alteration of cognitive and emotional processes throughout the brain markedly impairing working memory,6 the activation of the HPA axis impacts almost every system in our body. Research shows that untreated chronic stress can result in serious health conditions including anxiety, depression, insomnia, muscle pain, high blood pressure, weakened immune system and obesity.7 The question that begs to be asked is just how prevalent stress really is. According to the American Psychological Associations Stress in America survey, 40 percent of all adults admit to lying awake at night because of stress. And whats worse, 33 percent reveal never having discussed ways to manage stress with their healthcare provider.8 Sex Differences and Estrogen Effects Sex differences in basal and stress HPA function and neuropathologies associated with HPA dysfunction suggest that the HPA axis is subject to gonadal influence.9 For example, stress-related mental illnesses such as major depressive disorder and posttraumatic stress disorder (PTSD) are twice as prevalent in women.10 Though the exact mechanisms are not yet fully understood (the vast majority of behavioral neuroscience research is conducted in male animals), a growing body of literature points to the role of estrogen in modulating the action of neurotransmitters and glucocorticoids described above. Several mechanisms could explain how estrogens may sensitize the PFC to the detrimental effects of stress. First, high estrogen levels may exacerbate the effects of stress-induced glucocorticoid release.11 Another means by which estrogens may exert their influence is through the dopaminergic system. In this scenario, both high and lowestrogen females present an increased sensitivity to stress (see figure 1).12 Minimizing the Impact of Stress and Hormonal Imbalance The key to managing stress is recognizing and changing the behaviors that cause it.13 However, modifying behavior, lifestyle, or even eating habits can be challenging especially while undergoing stressful events! For example, physical activity is known to increase the bodys production of endorphins (feel-good neurotransmitters in the brain) and can help treat mild forms of depression and anxiety.14 Unfortunately, prioritizing exercising during intense periods of stress is not something easily achieved by most people. And when it comes down to achieving hormonal balance, the challenge is even greater! But

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The stress - brain loop

attention perception short-term memory learning word finding cellular changes in the hippocampus

chronic stress
inadequate sleep poor nutrition emotional distress

increases glucocortoids

decreased regulation of cortisol

Figure 2: Stress and its effects on brain Function

certain herbs and supplements can help modulate our stress response and our estrogen levels. Adopt the Adaptogens Rhodiola, ginseng and ashwagandha (to name a few) belong to a class of medicinal herbs collectively known as adaptogens. Adaptogens are defined as a new class of metabolic regulators which increase the ability of an organism to adapt to environmental factors and to avoid damage from such factors.15 Despite an extensive amount of research in the USSR,16 the nonspecific concept of adaptogens has struggled for acceptance in western countries until recently, due to its contrast with some key concepts of modern pharmacology. However, since 1998 the term adaptogen is allowed as a functional claim by the US Food and Drug Administration and by the European Medicines Agency. Rhodiola Rhodiola rosea thrives at high altitudes in Arctic areas of Europe and

Asia17 and can provide a powerful antidote to the stresses of modern day life. Preparations of Rhodiola extracts are used world-wide to strengthen the bodys response to physical, mental, and emotional stressors. For example, it was approved in 1969 by the Pharmacological Committee of the Ministry of Health of the USSR for use as a stimulant against fatigue by patients who suffered asthenic (personality disorder) states and by healthy people who showed astheny during periods of high mental exertion or after intensive physical work, and it is also commonly used in the medical regime of some European countries18 A number of studies have shown that Rhodiola can dramatically reduce mental and physical fatigue under stressful conditions. In one study, R. rosea extract (170 mg/day) was given to a group of 56 physicians on night duty. Using measures of cognitive and memory function, such as associative thinking, short-term memory,

calculation, and speed of audiovisual perception, the researchers found a statistically significant reduction of stress-induced fatigue after just two weeks of supplementation.19 A series of studies also revealed that Rhodiola can help increase attention to detail-oriented tasks by improving concentration over a prolonged period.20 A one-time dose of R. rosea of 300 mg or more, significantly decreased the percentage of errors made in a proofreading test, particularly over an eight-hour period.21 Recent research highlights the potent antioxidant effects of Rhodiola on nervous system cells. The scientists from Jiangsu Institute of Nuclear Medicine in China concluded that salidroside (an active ingredient found in Rhodiola) could be used for the prevention or treatment of neurodegenerative disease implicating oxidative stress.22 Other benefits attributed to R. rosea include: enhancing healthy sleep,23 relieving

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anxiety,24 lifting depressed mood,25 and maintaining blood sugar within an optimal range.26 Ashwagandha Ashwagandha (Withania somnifera) is one of the best known medicinal herbs originating from the Ayurvedic tradition. In traditional Indian medicine, ashwagandha is considered a panacea and it is used as a treatment for an array of ailments such as: stress, fatigue, pain, diabetes, gastro-intestinal and rheumatologic disorders.27 Clinical studies confirm the neuroprotective potential of this adaptogenic herb. It has been shown to prevent damage to neurons and improves neurological function in the presence of stress.28,29,30 In a double blind, randomized, placebo-controlled clinical trial assessing the effects of ashwagandha in 130 chronically stressed subjects over a 60-day period (125-500 mg/ day), a significant improvement of scores on a standardized measurement of stress intensity, and biomarkers associated with cardiovascular health was reported. Moreover, the subjects that received 500 mg of ashwagandha daily had cortisol levels nearly 30% lower than those in the placebo group, and their DHEA levels were also significantly higher.31 Siberian ginseng Siberian ginseng (Eleutherococcus senticosus), constitutes another example of a widely known and welldocumented adaptogen. While it is not technically a true ginseng botanical, E. senticosus shares similar beneficial properties with its close relatives from the Panax family of plants.32 The European Medicines Agency classifies this herb as a tonic for invigoration in fatigue and impairment, in decreasing capability and power of concentration as well as in reconvalescence.33 Modulating Estrogens As we have seen, balancing estrogen levels is important in modulating the stress response. Supporting estrogen metabolism by increasing sulforaphane consumption and modulating their activity with phytoestrogen consumption (plant-based estrogen-

like substances) can help achieve that goal. Since phytoestrogens resemble estradiol in their chemical structure and function, they can help substitute for a womans declining levels of estrogens.34 In the case of high estrogen levels, phytoestrogens may offer some protection by blocking the action of endogenous estrogens by interacting with some members of the estrogen receptor family.35 Sulforaphane Broccoli is a plentiful source of glucosinolates, which are converted enzymatically into isothiocyanates. One of the primary isothiocyanates in broccoli is sulforaphane. This plant chemical has been shown to increase the production of glutathione S-transferase and other phase II detoxification enzymes, enhance antioxidant status, and protect animals against chemically induced cancer.36 These powerful enzymes are responsible for metabolizing estrogens and eliminating other harmful toxins and carcinogens from the body. Hops Although the hops plant (Humulus hupus) owes most of its fame to its role in brewing beer, it has a long tradition of use as a sedative and

hypnotic herb.37 More recently, an extract of the hops cone has been found to contain a previously unknown class of nonsteroidal phytoestrogens (prenylflavonoids) of which 8-prenylnaringenin (8-PN) is the most potent. Clinical studies demonstrate that 8-PN is significantly more potent than the isoflavones daidzein and genistein, but marketedly less estrogenic than estradiol.38 Hops extract provides the ideal balance between potency and safety when it comes to modulating estrogens levels. Stressful events can lead to immediate and marked impairments in working memory and other cognitive functions which depend on a balanced neurochemical state. Research has shown that this impairment is driven by increased catecholamines signaling, which may be further modulated or exacerbated by changes in steroid hormone levels. A safe and natural strategy to support the bodys capacity to cope with stress through the use of science-based adaptogenic herbs, standardized for their content in active ingredients and combined with the modulation of estrogen level, may help improve cognitive functions.

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References
1. Selye H. The Stress of Life (rev. edn.) 1976. New York: McGraw-Hill 2. Miller EK, Freedman DJ, Wallis JD. The prefrontal cortex: categories, concepts and cognition. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2002; 357 (1424): 112336. 3. Goldman-Rakic PS. Cellular basis of working memory. Neuron. 1995; 14: 477485. 4. De Kloet ER, Jols M, Holsboer F. Stress and the brain: from adaptation to disease. Nat. Rev. Neurosci. 2005; 6: 463475. 5. Shansky RM and Lipps J. Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex. Front Hum Neurosci. 2013; 7: 123. 6. Arnsten AFT. Stress signalling pathways that impair prefrontal cortex structure and function. Nat. Rev. Neurosci. 2009; 10: 410422. 7. Baum A and Polsusnzy D. Health Psychology: Mapping Biobehavioral Contributions to Health and Illness. Annual Review of Psychology. 1999; 50: 137-163. 8. American Psychological Association. Stress in America: Missing the Health Care Connection. Accessed May 2012, http://www.apa.org/news/ press/releases/stress/index.aspx 9. Viau V. Functional cross-talk between the hypothalamic-pituitary-gonadal and -adrenal axes. J Neuroendocrinol. 2002;14(6):506-13. 10. Becker JB, Monteggia LM, Perrot-Sinal TS, et al. Stress and disease: is being female a predisposing factor? J. Neurosci. 2007; 27: 1185111855. 11. Arnsten AFT. Stress signalling pathways that impair prefrontal cortex structure and function. Nat. Rev. Neurosci. 2009; 10: 410422. 12. Idem 13. Idem 14. American Psychological Association http://www.apa.org/helpcenter/understanding-chronic-stress.aspx 15. Fox KR. The influence of physical activity on mental well-being. Public Health Nutrition. 1999; 2: 411-418. 16. Samuelsson G and Bohlin L. Drugs of Natural Origin: A Treatise of Pharmacognosy, 6 ed., Swedish Academy of Phramaceutical Sciences, Stockholm, Sweden. 2009; 226-228. 17. Panossian A, Wikman G, Wagner H. Plant adaptogens. III. Earlier and more recent aspects and concepts on their mode of action. Phytomedicine. 1999; 6 (4): 287300. 18. Brown R, Gerbarg P, and Ramazanov Z. Rhodiola rosea: A Phytomedicinal Overview. Herbalgram. 2002; 56:40-52. 19. Khanum F, Bawa AS, Singh B. Rhodiola rosea: a versatile adaptogen. Comp. Rev. Food Sci. Food Saf. 2005: 4; 5562. 20. Darbinyan V, Kteyan A, Panossian A, et al. Rhodiola rosea in stress induced fatiguea double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine. 2000; 7(5):36571. 21. Brown R, Gerbarg P, and Ramazanov Z. Rhodiola rosea: A Phytomedicinal Overview. Herbalgram. 2002; 56:40-52. 22. Idem 23. Zhang L, Yu H, Sun Y, et al. Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. Eur J Pharmacol. 2007; 564(1-3):18-25. 24. Li T, Xu G, Wu L, Sun C. Pharmacological studies on the sedative and hypnotic effect of salidroside from the Chinese medicinal plant Rhodiola sachalinensis. Phytomedicine. 2007; 14(9):601-4. 25. Perfumi M. and Mattioli L. Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice. Phytother Res. 2007; 21(1):37-43. 26. Idem 27. Kim SH, Hyun SH and Choung SY. Antioxidative effects of Cinnamomi cassiae and Rhodiola rosea extracts in liver of diabetic mice. Biofactors. 2006; 26(3):209-19. 28. Mishra LC. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev. 2000; 5(4):334-46. 29. Cooley K. Naturopathic Care for Anxiety: A Randomized Controlled Trial ISRCTN78958974. PLoS ONE. 2009; 4(8): e6628. 30. Tohda C. Search for natural products related to regeneration of the neuronal network. Neurosignals. 2005; 14(1-2):34-45. 31. Choudhary MI. Cholinesterase inhibiting withanolides from Withania somnifera. Chem Pharm Bull, 2004; 52(11):1358-1361. 32. Auddy B. et al. A Standardized Withania Somnifera Extract Significantly Reduces Stress-Related Parameters in Chronically Stressed Humans: A Double-Blind, Randomized, Placebo-controlled Study. JANA. 2008;11(1):50-6. 33. Committee on Herbal Medicinal products (HMPC) European Medicines Agency. Assessment report for the Development of a Community Monograph and for Inclusion of Herbal Substance(s), Preparation(s) or Combinations thereof in the List - Eleutherococcus senticosus (Ruppr. et Maxim.) Maxim., radix. p.17 London. Doc. Ref. EMEA/HMPC/232403/2006 34. Lethaby AE, Brown J, Marjoribanks J et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2007; 17(4): CD001395. 35. Warren BS and Devine C. Phytoestrogens and Breast Cancer Fact Sheet. Program on Breast Cancer and Environmental Risk Factors, Cornell University, College of Veterinary Medicine Vet Box 31, Ithaca, NY. 2001; 14853-6401. 36. Shapiro TA, Fahey JW, Wade KL et al. Chemoprotective glucosinolates and isothiocyanates of broccoli sprouts: metabolism and excretion in humans. Cancer Epidemiol Biomarkers Prev. 2001; 10(5): 501-8. 37. De Keukeleire D, De Cooman L, Rong H et al. Functional properties of hop polyphenols. Basic Life Sci. 1999; 66:739-60. 38. Miyamoto M, Matsushita Y, Kiyokawa A et al. Prenylflavonoids: a new class of non-steroidal phytoestrogen (Part 2). Estrogenic effects of 8-isopentenylnaringenin on bone metabolism. Planta Med. 1998; 64(6): 516-9.

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CurcuMIND
Super-bioavailable curcumin enhanced with vitamin D for increased cognitive benefits

Stressed?
OrthoAdapt

ORTHOMOLECULAR RESEARCH

ADVANCED