Mini-Review • DOI: 10.1515/tnsci-2017-0014 • Translational Neuroscience • 8 • 2017 • 87-96 Translational Neuroscience Joseph Mathew Antony1*, Ian Weaver2, THE ESSENTIALS OF A GLOBAL Matthew Rueffer3, Najla Guthrie1, INDEX FOR COGNITIVE FUNCTION Malkanthi Evans1 Abstract 1KGK Science Inc. 1440, One London Place, Cognition is comprised of the faculties: perception, creativity, intuition, and ratiocination. Optimal levels of London, ON, N6A 5R8, Canada cognition are needed for independent functioning and balanced living. With an aging population that continues 2Department of Psychology and Neuroscience, to grow, dietary supplements that tilt the balance towards maintenance of cognition are being marketed for Dalhousie University, Halifax, NS B3H 4R2, Canada vulnerable populations facing these challenges. Randomized clinical trials provide the causal inference necessary 3Robarts Clinical Trials, 100 Dundas St, to define the efficacy of emerging nutraceuticals. Cognition testing, in particular, requires a battery of tests that London, ON N6A 5B6 encompass all brain regions involved in cognition so as to provide endpoints necessary for product validation. The lack of well controlled studies for comparison analyses, limited sample sizes, ambiguous dosages, and poor cognitive measures result in data that cannot be compared across studies to determine the efficacy of supplements claiming to enhance cognition. Clinical trials for the nutraceutical industry should consider the multifaceted nature of supplements, where clinical endpoints must be comprehensive while remaining feasible. Combining endpoints of cognition with physiological biomarkers of immunity and metabolism to arrive at a global index for cognitive health may be necessary for claim substantiation in order to fully justify and scientifically validate improvements in cognitive health. The issues and needs of a global index will be discussed here. Keywords Received 3 April 2017 • Cognition • Dietary Supplements • Neuropsychological Tests • Global Index accepted 2 August 2017 The complexity of defining good etc. [3], making it easier to define the absence hypothesized to affect cognitive function [5]. A cognitive health of mental disorders. Conversely, defining ‘good variety of phytochemicals including resveratrol, Cognition is the ability to think, learn and cognitive health’ provides a bigger challenge as green tea extract, beta carotene, as well as remember, thus forming the basis for an it is not immediately clear what contributes to chromium picolinate and antioxidants have individual’s capacity for perception, reasoning, good/optimal cognitive health, demonstrating supporting clinical evidence that demonstrates acts of creativity, problem solving and possibly the fact that it is easier to screen for the improvements in cognition (Figure 1). intuition [1]. Good cognitive health, particularly presence of disease rather than the absence Clinical trials evaluating the efficacy of dietary during aging, is integral to maintaining of it. The aim of this brief review is to elucidate supplements embrace tools that measure independence and staying active. While the essentials of a global index by creating a cognitive functions, but are only useful if they modest age-related declines in cognition single composite endpoint based on cognitive, encompass all aspects related to the polyvalent and memory are normal, health problems immune, physiological and emotional markers. nature of nutrients. This is exemplified by underlying these symptoms can raise concerns clinical trials evaluating the efficacy of nutrients Current modes for measuring necessitating interventions. Approximately 30 having mostly utilized the mini mental state million adults, the majority of who are men cognitive health examination (MMSE) as an outcome measure under the age of 50 years, take supplements While pharmaceutical management of of cognitive performance, when in actuality for brain health [2]. Consequently, there is a cognition mostly targets dementia related to this is a measure of cognitive impairment. As need to understand whether existing tools and ageing and disease, nutraceutical modulation nutritional effects are generally subtle, the biomarkers can confidently support the efficacy aims to maintain cognition and prevent application of tests that measure degree of of nootropics in the nutraceutical industry. cognitive decline in healthy individuals. impairment when evaluating performance in an As it pertains to mental health, many major The impact of probiotics on mood has un-impaired population is highly questionable psychiatric disorders have reliable indicators been demonstrated in clinical studies [4] as this method will most likely not capture in depression, stress, burnout, panic disorders, with gut microbiota dysbiosis having been sufficient variability in performance scores to * E-mail: [email protected] © 2017 Joseph Mathew Antony et al., published by De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. 87 Translational Neuroscience Figure 1: Nutrients and phytochemicals that have demonstrated clinically relevant improvement in cognition facilitate the detection of subtle effects [6]. in cognition tests, identified through increased compared to a placebo (3.4 vs. 0.5 respectively) Additionally, adult participants in nutrition levels of the Klotho gene variant [9]. [11]. Corroborating the aforementioned finding studies who are cognitively unimpaired fall Inconsistencies in results obtained using are the results of a longitudinal study of healthy within a range in several demographic features MMSE as a tool to detect meaningful differences individuals where the cognitive state of a cross- that likely have an impact on the efficacy of in cognitive function in nutrition studies have sectional sample was analyzed in response the nutrient intervention used. For example, been noted. Further, the pervasive use of MMSE to consumption of fruits and vegetables. race was directly associated with cognitive in clinical trials evaluating dietary supplements Here, the MMSE used as a measure of global functioning and indirectly associated through that assess cognition have mostly included cognitive function uncovered an effect of diet social risk factors such as education and health patients with various cognitive impairments, on cognition [12]. insurance [7], thereby influencing the outcome resulting in a lack of studies showing a direct Randomized Controlled Trials in of cognitive testing, it is therefore necessary for comparison between supplements. For study design to be cognizant of these variables. example, two years of supplementation Clinical Nutrition Inclusion/exclusion criteria must allow for with folic acid and vitamin B12 did not affect The gold standard for scientific evidence is screening of individuals presenting a genetic cognitive performance in 2919 elderly the randomized controlled trial (RCT), which risk of cognitive decline, identified through participants with elevated homocysteine levels has been unequivocally accepted in order to polymorphisms in Brain-Derived Neurotrophic [10]. In contrast, elderly individuals suffering make valid health claims in the nutraceutical Factor (BDNF), Catechol-O-methyltransferase from chronic fatigue syndrome showed a and pharmaceutical industries. However, the (COMT) and Apolipoprotein (APOE) genes [8], significant improvement in MMSE score after design of a clinical trial should be subject to the or contrariwise presenting a genetic advantage supplementation with acetyl L-carnitine product being tested. Pharmaceutical drugs 88 Translational Neuroscience typically have fewer principal endpoints and/or accuracy and error rates were not provided and who supplemented with B vitamins and outcome measures that are large. In contrast, the reproducibility, validity and adoption of placebo, regardless of the duration of the due to the multifaceted nature of nutrients, cultural and language-sensitive issues related study or the battery of cognitive tests used dietary supplements exert their effects in many to the tests were not considered [1]. [17]. Similar results have been reported after tissues with effects realised over months and Non-verbal intelligence, normally assessed supplementation with eicosapentaenoic years. in children in nutritional intervention studies, acid and docosahexaenoic acid for 26 weeks have generally used internationally recognized in 302 cognitively healthy individuals aged Challenges in Randomized culture-fair tests such as Raven’s Colour 65 years or older and subjected to a battery Controlled Trials Progressive Matrices and Comprehensive Test of neuropsychological tests [18]. Cognitive Dietary supplements targeting brain health and of Non-verbal Intelligence [15]. Application of functions measured by Continuous Attention cognition, particularly in healthy populations, these cognition tests to evaluate micronutrient Test, Four-Choice Reaction Time, Digit- may have a large effect size in RCTs, if the study supplementation in children aged 5-15 years Symbol Substitution and Scanning Memory design includes a control group that receives did not demonstrate a consistent impact on Sets in 24 healthy elderly subjects (73 ± 5.6 an inadequate intake of an essential element. intelligence and long-term mental functions years) supplemented with folic acid for four However, this is not an ethical concept and [15]. However, food fortified with multiple weeks did not show any