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1 | natural medicines, nutraceuticals and neurocognition |
2 | boca raton london new york crc press is an imprint of the taylor & francis group, an informa business advances in natural medicines, nutraceuticals and neurocognition edited by con stough and andrew scholey |
3 | crc press taylor & francis group 6000 broken sound parkway nw, suite 300 boca raton, fl 33487-2742 © 2013 by taylor & francis group, llc crc press is an imprint of taylor & francis group, an informa business no claim to original u.s. government works version date: 20121115 international standard book number-13: 978-1-4398-9362-3 (ebook - pdf) this book contains information obtained from authentic and highly regarded sources. reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. the authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. if any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. except as permitted under u.s. copyright law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information stor- age or retrieval system, without written permission from the publishers. for permission to photocopy or use material electronically from this work, please access www.copy- right.com (http://www.copyright.com/) or contact the copyright clearance center, inc. (ccc), 222 rosewood drive, danvers, ma 01923, 978-750-8400. ccc is a not-for-profit organization that pro- vides licenses and registration for a variety of users. for organizations that have been granted a pho- tocopy license by the ccc, a separate system of payment has been arranged. trademark notice: product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. visit the taylor & francis web site at http://www.taylorandfrancis.com and the crc press web site at http://www.crcpress.com |
4 | xii editors in 2007. prof. scholey has been lead investigator in a series of studies into the human biobehavioral effects of natural products and their neurocognition-enhancing and anti-stress/ anxiolytic properties. he has attracted millions of dollars in research funding, including as chief investigator on national competitive grants from the united kingdom, europe, and australia, as well as from many industry bodies in europe, north america, asia, and australia. he has acted as advisor to numerous industry bodies, ilsi europe and ilsi south east asia, and has reported to the uk parliamentary forum on diet and health. |
5 | xiii joanne bradbury school of health and human sciences southern cross university lismore, new south wales, australia david camfield centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia dennis chang center for complementary medicine research school of science and health university of western sydney penrith, new south wales, australia ben colagiuri school of psychology the university of sydney sydney, new south wales, australia vanessa cropley melbourne neuropsychiatry centre the university of melbourne melbourne, victoria, australia melissa finn centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia crystal f. haskell department of psychology brain, performance, and nutrition research centre northumbria university newcastle upon tyne, united kingdom philippa jackson faculty of health and life sciences brain, performance, and nutrition research centre northumbria university newcastle upon tyne, united kingdom james kean centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia david o. kennedy department of psychology brain, performance, and nutrition research centre northumbria university newcastle upon tyne, united kingdom rong luo chengdu university of traditional chinese medicine chengdu, sichuan, people’s republic of china helen macpherson centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia annette e. maczurek department of pharmacology school of medicine university of western sydney penrith, new south wales, australia contributors |
6 | xiv contributors gerald münch department of pharmacology and molecular medicine research group school of medicine university of western sydney penrith, new south wales, australia lezanne ooi department of pharmacology school of medicine university of western sydney penrith, new south wales, australia lauren owen centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia matthew pase centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia mili patel department of pharmacology school of medicine university of western sydney penrith, new south wales, australia andrew pipingas centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia jerome sarris faculty of medicine department of psychiatry the melbourne clinic the university of melbourne melbourne, victoria, australia andrew scholey centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia hemant k. singh central drug research institute lucknow, india and lumen research foundation chennai, india creina s. stockley the australian wine research institute urrbrae, south australia, australia con stough centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia keith a. wesnes bracket global goring-on-thames, united kingdom and division of psychology northumbria university newcastle, united kingdom and centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia andrea zangara soho-flordis international sydney, new south wales, australia and centre for human psychopharmacology swinburne university of technology melbourne, victoria, australia |
7 | part i methodologies to measure cognition in natural medicine trials |
8 | natural medicines, nutraceuticals and neurocognition recognition, the time actually taken to successfully retrieve the information from memory. this important aspect of memory has been overlooked by traditional tests which cannot make this assessment, but this aspect of memory declines markedly and independently of accuracy with normal aging, and is severely compromised in many debilitating diseases such as dementia (e.g., simpson et al., 1991; nicholl et al., 1994; wesnes et al., 2002). further in mci, such slowed speed of retrieval of information is an early characteristic of the disease (nicholl et al., 1995), which also can respond to pharmacological treatment (newhouse et al., 2012). automation also provides the same benefits for tests of the ability to retain information in working memory, as the role of working memory is to facilitate the performance of ongoing tasks; and clearly it is not just the ability to correctly retain the information that is important but also the time taken to decide correctly retrieve this information, something which cannot be assessed with traditional tests such as digit span. a fur- ther important benefit of assessing speed is that it permits “speed-accuracy trade- offs” to be identified, which helps to avoid misinterpretations of study findings. guidelines for establishing cognition enhancement our understanding of cognition enhancement is at an early stage, and there are few, if any, established criteria. for a compound to be established as an enhancer of one or more aspects of cognitive function, the following criteria have been recently pro- posed (wesnes, 2010). 1. improvements must be identified by well recognized and extensively vali- dated tests of cognitive function. 2. improvements should be to one or more major domains of cognitive function. 3. improvements must be seen on core measures of task performance, and any suggestions of speed-accuracy trade-offs should be interpreted with caution. 4. improvements in one cognitive domain should not occur at the cost to another. 5. improvements should not be followed by rebound declines. 6. improvements should be of magnitudes which are behaviorally and clini- cally relevant. 7. improvements should not be subject to tachyphylaxis over the period for which the treatment is intended to be used. 8. self-ratings are of interest, and may be used as supportive evidence, but are not sufficient in the absence of objective test results. cognitive function and normal aging there is much debate about the declines in the quality of mental functioning which accompany aging. a traditional approach has been to compare young adults (e.g., 18–25 years) to the elderly (e.g., 65–80 years), and much research has shown that a |
9 | natural medicines, nutraceuticals and neurocognition for choice reaction time. as can be seen, the declines are linear across the age range, starting in the late 1920s, which is entirely consistent with the work of salthouse. further, a decline of one standard deviation can be seen by early middle age, and by at least another by the 1960s. an important aspect of the latter findings is that the individuals tested had participated in clinical trials as healthy volunteers, and had thus undergone extensive medical screening. these individuals were thus free of major medical or psychiatric conditions, and such declines actually represent a best case for normal aging. the same tests have been administered to patients with a variety of conditions including hypertension, heart disease, fibromyalgia, adhd, epilepsy, narcolepsy, chronic fatigue syndrome, schizophrenia, and multiple sclerosis. when each of these populations is compared to age-matched healthy controls, cogni- tive deficits of one or more standard deviations are seen on, for example, the ability to focus attention (wesnes, 2006). this body of research therefore indicates that major aspects of cognitive function decline with normal aging, and that a variety of mental and physical illnesses will further exacerbate this deterioration. in recognition of cognitive declines in normal aging, the u.s. national institute of mental health (nimh) set up a working group in 1986 to agree criteria for the condition of age-associated memory impairment (aami) (crook et al., 1986). the aims of the criteria were to identify those elderly individuals (50 years and older) who were aware of memory loss that had occurred gradually, who scored at least one standard deviation below the normal score for that of the young on a widely recognized test of memory (e.g., the benton visual retention test; the logical memory subtest of the wechsler memory scale, etc.), who showed evidence of adequate intel- lectual functioning (using the vocabulary subtest of the wechsler adult intelligence scale), and who showed no evidence of dementia (as assessed by a mini-mental status examination score of 24 or above). the exclusion criteria were designed to exclude those whose poor performance was not due to normal aging, for example, being secondary to disease or actually being dementia. a number of clinical trials subse- quently evaluated the effect of various pharmacological and herbal treatments for aami, with some limited success (for review, see wesnes and ward, 2000). the fourth edition of the diagnostic and statistical manual of mental disorders of the american psychiatric association (dsm-iv) identified age-associated cognitive decline (aacd) as a condition which may be a focus of clinical attention (diagnostic code 780.9). the advantage of aacd is that it extended the range of impairments from simply memory to cognitive functioning in general, thus encompassing atten- tion, information processing, and a range of other aspects now known to deteriorate with aging. the definition was for a “decline in cognitive functioning consequent to the aging process that is within normal limits given the person’s age. individuals with this condition may report problems remembering names or appointments or may experience difficulty in solving complex problems. this category should be consid- ered only after it has been determined that the cognitive impairment is not attribut- able to a specific mental disorder or neurological complaint” (p. 684, dsm-iv). however, regulatory bodies have not accepted aami, aacd, or other similar conditions as legitimate conditions for drug registration, and much of the focus of drug development in the past decade has moved to the condition of mci (petersen and morris, 2005). however, the criteria for an individual to be classified for this |
10 | natural medicines, nutraceuticals and neurocognition dementias (e.g., lebars et al., 1997; napryeyenko and borzenko, 2007), a very large trial has shown that the compound is not able to prevent the development of dementia (dekoskey et al., 2008); though it has to be acknowledged that none of the registered treatments for the disease have been demonstrated to do this either. a follow-up publication on the dekoskey study, however, showed that gingko did not prevent the rates of cognitive decline over a median 6 year period in individuals aged 72–96 years (snitz et al., 2009). on balance, while ginkgo clearly does not prevent cognitive decline in elderly individuals, or prevent the onset of dementia, it does appear to have beneficial cognitive effects on younger populations, and also patients with dementia. other research programmes have evaluated the effects of a combination of stan- dardized extracts of ginkgo biloba and panax ginseng, showing improvements to working and episodic memory with acute doses in volunteers (kennedy et al., 2001, 2002), patients with neurasthenia (wesnes et al., 1997), and middle-aged volunteers (wesnes et al., 2000). in each of these four studies, statistically reliable improvements were seen to the ability to successfully hold and retrieve information in short-term (working) and long-term (episodic) memory. there were no improve- ments to attention, or to the speed with which the information could be retrieved from memory. in the wesnes et al. (2000) study, 256 healthy volunteers with a mean age of 56 years (range 38–66) were tested in a 14 week randomized placebo-controlled double-blind study, and over the period of the study, an overall improvement in the ability to store and retrieve information in memory of 7.5% was identified. a subse- quent analysis of these data showed that the magnitude of the improvement was suf- ficient to counteract the decline that would have occurred in the population compared to a younger population of 18–25 years. this is evidence that age-related cognitive declines can be reversed by natural substances, which can be purchased over the coun- ter in pharmacies, and offers individuals the chance to self-medicate with relatively safe substances to maintain cognitive function into late middle age. in addition to the above research, a wide range of other natural substances have been found to improve cognitive function in the young and elderly, including caffeine (e.g., smit and rogers, 2000; haskell et al., 2005; smith et al., 2005), pyro- glutamic acid (grioli et al., 1990), phosphatidylserine (crook et al., 1991), guanfa- cine (mcentee et al., 1991), huperzine (wang, 1994; zangara et al., 2003), ginseng + vitamins (neri et al., 1995; wesnes et al., 2003), panax ginseng (kennedy et al., 2001b; 2007; sunram-lea et al., 2004), acetyl-l-carnitine (salvioli and neri m, 1994; thal et al., 1995), bacopa monniera (maher et al., 2002; stough et al., 2008), sage (tildesley et al., 2003; 2005; scholey et al., 2008), melissa officinalis (kennedy et al., 2002; 2003), alpha lipoic acid (hager et al., 2001), guarana (kennedy et al., 2004), essential oils and aromas (moss et al., 2003, 2008), pycnogenol (ryan et al., 2008), and thiamine (haskell et al., 2008). benefits have also been identified with breakfast cereals (wesnes et al., 2003; ingwersen et al., 2007), energy drinks (e.g., scholey and kennedy, 2004), and chewing gum (wilkinson et al., 2002). the level of evidence required in this field should not differ from any other field of clinical research. therefore, randomized, double-blind, placebo-controlled trials must be employed, and cognitive test systems utilized, which are fit-for-purpose for the requirement of detecting enhancements to various aspects of cognitive function. only properly characterized substances should be tested, and standardized extracts |
11 | natural substances as treatments for age-related cognitive declines kennedy do, scholey ab, and wesnes ka (2002). modulation of cognition and mood fol- lowing administration of single doses of ginkgo biloba, ginseng and a ginkgo/ginseng combination to healthy young adults. physiology and behaviour 75: 1–13. kennedy do, wake g, savelev s, tildesley ntj, perry ek, wesnes ka, and scholey ab (2003). modulation of mood and cognitive performance following acute adminis- tration of single doses of melissa officinalis (lemon balm) with human cns nico- tinic and muscarinic receptor-binding properties. neuropsychopharmacology 28: 1871–1881. kleijnen j and knipschild p (1992). ginkgo biloba for cerebral insufficiency. british journal of clinical pharmacology 34: 352–358. le bars pl, katz mm, berman n, itil tm, freedman am, and schatzberg af (1997). a placebo-controlled, double-blind, randomised trial of an extract of ginkgo biloba for dementia. north american egb study group. journal of the american medical association 278(16): 1327–1332. mackworth jf (1965). the effect of amphetamine on the detectability of signals in a vigilance task. canadian journal of psychology 19: 104–109. maher b (2008). poll results: look who’s doping. nature 452: 674–675. maher bfg, stough c, shelmerdine a, wesnes ka, and nathan pj (2002). the acute effects of combined administration of ginkgo biloba and bacopa monneira on cognitive func- tion in humans. human psychopharmacology 17: 163–164. maurer k, ihl r, dierks t, and frolich l (1997). clinical efficacy of ginkgo biloba special extract egb 761 in dementia of the alzheimer type. journal of psychiatric research 31(6): 645–655. mcentee wj, crook th, jenkyn lr, petrie w, larrabee gj, and coffey dj (1991). treatment of age-associated memory impairment with guanfacine. psychopharmacology bulletin 27: 41–46. moss m, cook j, wesnes ka, and duckett p (2003). aromas of rosemary and lavender essen- tial oils differentially affect cognition and mood in healthy adults. international journal of neuroscience 113: 15–38. moss m, howarth r, wilkinson l, and wesnes ka (2006). expectancy and the aroma of roman chamomile influence mood and cognition in healthy volunteers. international journal of aromatherapy 16: 63–73. moss mc, scholey ab, and wesnes ka (1998). oxygen administration selectively enhances cognitive performance in healthy young adults: a placebo-controlled double-blind crossover study. psychopharmacology 138: 27–33. napryeyenko o and borzenko i (2007). ginkgo biloba special extract in dementia with neuropsychiatric features. a randomised, placebo-controlled, double-blind clinical trial. arzneimittelforschung 57: 4–11. neri m, andermacher e, pradelli jm, and salvioli g (1995). influence of a double blind phar- macological trial on two domains of well-being in subjects with age associated memory impairment. archives of gerontology and geriatrics 21: 241–252. newhouse p, kellar k, aisen p, white h, wesnes k, coderre e, pfaff a, wilkins h, howard d, and levin ed (2012). nicotine treatment of mild cognitive impairment: a six-month double-blind pilot clinical trial. neurology 84: 91–101. nicholl cg, lynch s, kelly ca, white l, simpson l, simpson pm, wesnes ka, and pitt bmn (1995). the cognitive drug research computerised assessment system in the evaluation of early dementia—is speed of the essence? international journal of geriatric psychiatry 10: 199–206. oken bs, storzbach dm, and kaye ja (1998). the efficacy of ginkgo biloba on cognitive function in alzheimer’s disease. archives of neurology 55(11): 1409–1415. petersen rc and morris jc (2005). mild cognitive impairment as a clinical entity and treat- ment target. archives of neurology 62: 1160–1163. |
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14 | measuring and interpreting the efficacy of nutraceutical interventions the importance of diet and lifestyle during aging. chronic nutraceutical interventions hold great promise in ameliorating age-related cognitive decline because they simul- taneously target multiple cellular mechanisms of cognitive decline. many natural sub- stances already identified through in vivo as well as clinical studies have been found to have potent anti-oxidant and anti-inflammatory properties as well as being of benefit to the cardiovascular system (ghosh and scheepens, 2009; head, 2009; kidd, 1999). in order to be able to accurately assess and interpret the clinical efficacy of these natu- ral substances, it is recommended in the following review that highly accurate and spe- cific cognitive tests are needed, together with the creation of normative databases that may be used to interpret clinical data in terms of years of cognitive function recovered. tests of cognitive function in the elderly traditional ways of measuring cognitive decline in the elderly have involved clinical neuropsychological tests, tests that were often designed for the diagnosis of demen- tia. commonly used dementia assessment scales include the mini mental state exam (mmse; folstein et al., 1975), the clinical dementia rating scale (morris, 1997) and the cognitive subtest of the alzheimer’s disease assessment scale (adas-cog; mohs et al., 1983). such scales involve structured interviews to determine the presence of dementia, and if present then the severity of dementia symptoms. while these scales may be useful in the diagnosis of dementia, they lack the sensitivity to be able to assess cognitive decline in the normal population, and hence a strong ceiling effect would be expected. another limitation of these clinical assessment scales is that they primarily assess global cognitive function, as opposed to specific cognitive domains that may be disproportionately affected by the aging process. further, these tests often rely on pen and paper recording, which lacks the measurement precision associated with modern computerized testing. for these reasons it is recommended that computerized tests that target spe- cific cognitive abilities and have a high degree of sensitivity to fluctuations in cognitive function be used for testing the efficacy of interventions for age-related cognitive decline, rather than the more traditional dementia assessment scales. the cognitive drug research (cdr; wesnes et al., 1999) neuropsychological assessment battery has previously been found to be a particularly sensitive measure for the detection of changes to cognitive function associated with chronic nutraceutical and dietary interventions (ryan et al., 2008; stough et al., 2008; wesnes et al., 2000). the computerized mental performance assessment system (compass; scholey et al., 2010), which was developed at northumbria university, united kingdom, has also been found to be a sensitive measure in nutraceutical intervention trials, as has the cambridge neuropsychological test automated battery (cantab; cambridge cognition, cambridge, united kingdom). using large normative samples, the cantab has been found to be sensitive enough to detect declines in cognitive ability associated with normal aging as well as mild cognitive impairment preceding dementia (égerházi et al., 2007; robbins et al., 1994). more recently our laboratory has developed a neuropsychological assessment bat- tery designed specifically for the assessment of age-related cognitive decline, the swinburne university computerized cognitive aging battery (succab; pipingas |
15 | natural medicines, nutraceuticals and neurocognition et al., 2008, 2010). the succab is a computerized test battery consisting of nine tasks designed to capture the range of cognitive functions that decline with age: immediate/ delayed word recall, simple reaction time, choice reaction time, immediate/delayed recognition, visual vigilance, n-back working memory, stroop color-word, spatial working memory, and contextual memory (pipingas et al., 2010). in preliminary stud- ies from our laboratory, the tasks contained in the succab have been found to be highly sensitive to age-related cognitive decline (pipingas et al., 2008). comparing the effects of nutraceutical interventions when reporting the results of timed cognitive tasks times, it is informative to not only state the results of parametric statistical tests and p-values but also report the average millisecond improvement that is observed in the treatment group. further, if the mean difference in reaction times has also been found to change in the placebo group, then the mean change in the treatment group above and beyond the change observed in the placebo group is the most informative metric. an example of reported millisecond improvements in succab tasks that were found to be associated with a chronic intervention is provided by pipingas et al. (2008). in a randomized, placebo-controlled trial, pipingas et al. (2008) investigated the cogni- tive effects associated with 5 weeks supplementation with the pinus radiata bark extract enzogenol® in 42 males aged 50–65 years. significant differences between the treat- ment and placebo groups were found for succab spatial working memory (swm) and immediate recognition memory. the average reduction in reaction time for the swm task in the enzogenol group was found to be 65 ms, while reaction times for the control group were unchanged. similarly, for succab immediate recognition memory, the average reduction in reaction time for the enzogenol group was found to be 60 ms, while the reaction time in the control group increased by 7 ms (pipingas et al., 2008). the same approach can also be used for computerized cognitive tests that are scored according to accuracy (percent correct). an example of improvements to swm accu- racy associated with a nutraceutical intervention is provided by stough et al. (2008). in a 90 day randomized placebo-controlled trial, stough et al. (2008) investigated the cognitive effects of bacopa monniera in 62 participants aged 18–60 years. significant differences between the treatment and placebo groups were found for change in cdr swm accuracy over the 3 month period. the average improvement in accuracy for the swm task in the bacopa monniera group was found to be 5.44%, while the aver- age improvement in the control group was found to be 2.3%. if we make the assump- tion that the average improvement in accuracy for the control group is a measure of improvement due to practice effects, then we can see that there is still a 3.14% improvement observed in the treatment group above and beyond this value. interpretation of cognitive change in terms of cognitive aging when baseline normative data are collected in regard to the results of computer- ized cognitive tests across a wide age range, the regression coefficient of age can be compared with the treatment effect when a nutraceutical intervention is applied. |
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17 | measuring and interpreting the efficacy of nutraceutical interventions pase, m. p., pipingas, a., kras, m., nolidin, k., gibbs, a. l., wesnes, k. a., scholey, a. b., and stough, c. (2010). healthy middle-aged individuals are vulnerable to cognitive defi- cits as a result of increased arterial stiffness. journal of hypertension, 28(8), 1724–1729. pipingas, a., harris, e., tournier, e., king, r., kras, m., and stough, c. k. (2010). assessing the efficacy of nutraceutical interventions on cognitive functioning in the elderly. current topics in nutraceutical research, 8(2–3), 79–87. pipingas, a., silberstein, r. b., vitetta, l., van rooy, c., harris, e. v., young, j. m., frampton, c. m., sali, a., and nastasi, j. (2008). improved cognitive performance after dietary supplementation with a pinus radiata bark extract formulation. phytotherapy research, 22(9), 1168–1174. price, d. l. and sisodia, s. s. (1998). mutant genes in familial alzheimer’s disease and trans- genic models. annual review of neuroscience, 21, 479–505. rabbitt, p. and lowe, c. (2000). patterns of cognitive ageing. psychological research, 63, 308–316. reid, l. m. and maclullich, a. m. j. (2006). subjective memory complaints and cognitive impair- ment in older people. dementia and geriatric cognitive disorders, 22(5–6), 471–485. robbins, t. w., james, m., owen, a. m., sahakian, b. j., mcinnes, l., and rabbitt, p. (1994). cambridge neuropsychological test automated battery (cantab): a factor analytic study of a large sample of normal elderly volunteers. dementia, 5(5), 266–281. ryan, j., croft, k., mori, t., wesnes, k., spong, j., downey, l., kure, c., lloyd, j., and stough, c. (2008). an examination of the effects of the antioxidant pycnogenol on cog- nitive performance, serum lipid profile, endocrinological and oxidative stress biomark- ers in an elderly population. journal of psychopharmacology, 22(5), 553–562. salthouse, t. a. (1996). the processing-speed theory of adult age differences in cognition. psychological review, 103 (3), 403–428. sarkar, d. and fisher, p. b. (2006). molecular mechanisms of aging-associated inflammation. cancer letters, 236(1), 13–23. schaie, k. w. (1996). intellectual development in adulthood: the seattle longitudinal study. intellectual development in adulthood: the seattle longitudinal study. cambridge university press, new york, ny. scholey, a., ossoukhova, a., owen, l., ibarra, a., pipingas, a., he, k., roller, m., and stough, c. (2010). effects of american ginseng (panax quinquefolius) on neurocogni- tive function: an acute, randomised, double-blind, placebo-controlled, crossover study. psychopharmacology, 212(3), 345–356. schretlen, d., pearlson, g. d., anthony, j. c., aylward, e. h., augustine, a. m., davis, a., and barta, p. (2000). elucidating the contributions of processing speed, executive ability, and frontal lobe volume to normal age-related differences in fluid intelligence. journal of international neuropsychological society, 6, 52–61. shammi, p., bosman, e., and stuss, d. t. (1998). aging and variability in performance. aging, neuropsychology, and cognition, 5(1), 1–13. stough, c., downey, l. a., lloyd, j., silber, b., redman, s., hutchison, c., wesnes, k., and nathan, p. j. (2008). examining the nootropic effects of a special extract of bacopa monniera on human cognitive functioning: 90 day double-blind placebo-controlled ran- domized trial. phytotherapy research, 22(12), 1629–1634. united nations. (2009). world population prospects: the 2008 revision, highlights, working paper no. esa/p/wp.210. department of economic and social affairs population division, new york. verhaeghen, p. and cerella, j. (2002). aging, executive control, and attention: a review of meta-analyses. neuroscience and biobehavioural reviews, 26, 849–857. wesnes, k. a., ward, t., ayre, g., and pincock, c. (1999). validity and utility of the cognitive drug research (cdr) computerised assessment system: a review following fifteen years of usage. european neuropsychopharmacology, 9(suppl. 5), s368. |
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19 | part ii vitamins and nutrients |
20 | natural medicines, nutraceuticals and neurocognition nac in the treatment of neuropsychiatric disorders cystine–glutamate antiporter group ii metabotropic glutamate receptors (mglur2/3) are located presynaptically on neurons in a large number of brain regions including the cortex, amygdala, hippocam- pus, and striatum [24], and play an important role in the regulation of the synaptic release of glutamate [25]. stimulation of mglur2/3 receptors by extracellular glutamate has an inhibitory effect on the synaptic release of glutamate [26]. extracellular levels of gluta- mate are maintained primarily by means of the cystine–glutamate antiporter [27]. this na+-independent antiporter is bound to plasma membranes and is found ubiquitously throughout the body, while being located predominantly on glial cells in the human brain [28]. cystine is the disulfide derivative of cysteine, consisting of two oxidized cysteine residues. when extracellular levels of cystine are increased in the brain, the antiporters on glial cells exchange extracellular cystine for intracellular glutamate. this leads to the stimulation of mglur2/3 receptors and inhibition of synaptic glutamate release. for this reason, cysteine prodrugs have the ability to reduce the synaptic release of glutamate, with important implications for the treatment of psychiatric disorders. inhibition of glutamate release in obsessive compulsive disorder a number of magnetic resonance spectroscopy (mrs) studies of obsessive compul- sive disorder (ocd) have revealed abnormal glutamate transmission in brain regions associated with cortico-striatal-thalamo-cortical (cstc) neurocircuitry. glx, a com- posite measure of glutamate, glutamine, homocarnosine, and gaba, has been found to be elevated in the caudate in ocd patients and to normalize again following ssri treatment [29–33]. this finding is consistent with the metabolic hyperactivity in cstc circuits, which is a known hallmark of ocd [34]. in contrast, glx levels have been found to be decreased in the anterior cingulate [35], a finding that paral- lels the inverse relationship between anterior cingulate and basal ganglia volume in ocd patients [36]. further evidence of elevated glutamate levels associated with ocd comes from a study by chakrabarty et al. [37], who reported increased levels of glutamate in the csf of drug-naive ocd patients. a number of studies have investigated the effects of glutamate-modulating drugs in the treatment of ocd spectrum disorders. in an open-label study using riluzole, a pharmacological agent which reduces synaptic glutamate release, pittenger et al. [38–39] reported a significant decrease in symptoms in 13 treatment-resistant ocd patients over a 12 week period. however, it has been found that not all anti- glutamatergic agents have been found to be effective, with topiramate (topamax) being found to exacerbate ocd symptoms and lamotrigine found to be ineffective [36]. there have also been mixed results found to date for the efficacy of memantine in the treatment of ocd [40]. this is most likely due to differences in the mecha- nism of action associated with each of these varied compounds. due to the effects of inhibiting synaptic glutamate release through glial cystine– glutamate exchange, nac also been investigated as a possible treatment for ocd. in a case study of a 58 year-old woman with sri-refractory ocd, lafleur et al. [41] reported that nac augmentation of fluvoxamine resulted in a marked reduction in |
21 | actions of n-acetylcysteine in the central nervous system ocd symptoms (y-bocs), and a clinically significant improvement in ocd symp- toms. the nac dose used in this study was titrated up from 1200 mg po daily to 3000 mg daily over a 6 week period, and then maintained at this dosage level for a fur- ther 7 weeks. it is interesting to note that a reduction of 8 points on the y-bocs scale was noticed after only 1 week of treatment, which is indicative of rapid onset of treat- ment effects in comparison to conventional ssri treatments for ocd, which may take several weeks for effects to become noticeable [42]. the possibility is also raised that there are acute effects associated with nac use, whereby a patient with ocd may be able to use nac on as-needed basis as an augmentation strategy for days when their symptoms are worse than usual. two clinical trials are currently underway to test the efficacy of nac in the treatment of ocd. costa and colleagues from the university of sao paulo are conducting a 16-week intervention study using 3000mg/day nac as an adjunctive treatment in ocd (nct01555970) while pittenger and colleagues from yale university are conducting a 12-week study using 2400mg/day nac for children aged 8–17 years (nct01172275). it is hoped that these studies will provide important data as to the efficacy of nac as treatment strategy for ocd. a disorder related to ocd, which is classified as part of the ocd spectrum dis- orders is trichotillomania, characterized by repetitive hair pulling. grant et al. [43] conducted a double-blind trial to assess the efficacy of nac (1200–2400 mg/day) in 50 participants with trichotillomania over a 12 week period. patients in the nac treat- ment group were found to have significantly greater reductions in hair-pulling symp- toms in comparison to placebo. significant improvements were observed from 9 weeks of treatment onwards. fifty-six percent of patients were found to be “much or very much improved” from the nac treatment group in comparison to only 16% assigned to the placebo group. another ocd spectrum disorder that nac use has been investi- gated as a potential treatment strategy is compulsive nail-biting. berk et al. [44] present three case studies where patients with a life-long history of compulsive nail-biting were found to benefit from nac treatment. in the first case study, a 46 years old woman is reported to stop nail-biting altogether over a 7 months period using a dosage of 1000 mg nac bid. in the second case study, a 44 years old woman is reported to stop nail biting after 4 months of treatment with nac 1000 mg bid, and to have not recommenced on a 2 month follow-up. in the third case study, a 46 years-old patient was not reported to stop nail-biting all together, but noticed a reduction in this behavior after 28 weeks after starting nac treatment. in addition to trichotillomania and nail-biting, nac has also been reported to be effective in the reduction of skin-picking behavior [45]. a number of concerns will need to be addressed in assessing the suitability of nac as a viable treatment option for ocd and related disorders, beyond a dem- onstration of efficacy. considering the high degree of comorbidity of depression with ocd [46], it is necessary in further research to investigate the effects of nac on mood. although preclinical evidence to date is promising, it suggests that ago- nists acting on the mglur2/3 receptors may dampen responses to stress and have a potential antidepressant effect [47–48], and the case study by lafleur et al. [41] also reported a decrease in depression in their patient as measured by the ham-d over the course of the trial. it may be important to monitor possible acute side effects of cognitive slowing that may result from over-regulation of glutamatergic tone with high-dose nac use, as has been occasionally reported in relation to riluzole [49]. |
22 | natural medicines, nutraceuticals and neurocognition normalization of extracellular glutamate in substance abuse increased glutamate transmission in the nucleus accumbens has been found to be a mediator of drug-seeking behavior, while in the case of repeated use of drugs of abuse such as cocaine, a reduction in basal levels of extracellular glutamate in the nucleus accumbens are also observed [50,51]. alterations in cystine–glutamate exchange and metabotropic glutamate receptor activity has also been found to regulate vesicu- lar release of dopamine, another central neurotransmitter in reward-related behavior [26,52]. due to its effects in inhibiting the synaptic release of glutamate in the cns, nac has been investigated for use in the treatment of substance abuse. preclinical research by baker et al. [52] revealed that systemic administration of nac to cocaine- treated rats restored extracellular glutamate levels in the nucleus accumbens in vivo. further, due to its effects on stimulating cystine–glutamate exchange, nac was found to block cocaine-primed reinstatement of drug-taking behavior. in rats withdrawn from cocaine use, there is a change in the ability to create synaptic plasticity, which is related to alterations in prefrontal glutamatergic innervation of the nucleus accumbens core. moussawi et al. [53] reported that the administration of nac to cocaine-treated rats reversed the deficit in synaptic plasticity by indirect stimulation of mglu2/3 and mglu5 receptors, responsible for long-term potentiation and long-term depression, respectively. in a pilot study investigating the effects of nac on craving in 15 cocaine- dependent humans, larowe et al. [54] reported that 600 mg nac administered at 12 h intervals over a 3 day period resulted in a significant reduction in the desire to use cocaine, interest in cocaine and cue viewing time, in the presence of cocaine- related cues. an open-label dose-ranging study of nac in the treatment of cocaine dependence in humans was conducted by mardikian et al. [55]. twenty-three treat- ment-seeking cocaine-dependent patients were assigned to either nac 1200, 2400, or 3600 mg/day over a 4 week trial. sixteen of the patients completed the trial, and the majority of these either stopped using cocaine or significantly reduced their intake by the end of the trial. the higher doses of 2400 and 3600 mg/day were found to be more effective in treating cocaine-dependence, with higher retention rates in comparison to the lower dose of 1200 mg/day. in human research using other drugs of abuse, similar results have been reported. in an open-label study investigating the use of nac in cannabis addiction, gray et al. [56] reported that 1200 mg nac twice daily resulted in significant reductions in mari- juana craving amongst 24 cannabis-dependent participants, as well as a trend-level reduction in marijuana usage, over a 4 week period. knackstedt et al. [57] conducted a study to investigate the effect of nicotine on cystine–glutamate exchange in the nucleus accumbens and the efficacy of nac in the treatment of nicotine addiction, using both animal and human data. over a 21 day period, rats self-administered nicotine intrave- nously and 12 h following the last nicotine dose the brains were removed and immu- noblotting was conducted in order to investigate changes in the catalytic subunit of the cystine–glutamate exchanger (xct) or the glial glutamate transporter (glt-1) in the nucleus accumbens, the ventral tegmental area (vta), the amygdala, and the pfc. decreased expression of the xct was observed in the nucleus accumbens and the vta, and decreased glt-1 expression was observed in the nucleus accumbens. in the second part of the study, 29 nicotine-dependent human subjects were administered |
23 | actions of n-acetylcysteine in the central nervous system 2400 mg nac/daily versus placebo for 4 weeks in a double-blind design. smokers treated with nac were found to report a greater reduction in the number of ciga- rettes smoked over the 4 week period in comparison to placebo, with a significant time × treatment group interaction when controlling for alcohol consumption. preclinical studies have demonstrated that levels of glutamate in the nucleus accum- bens mediate reward-seeking behaviors in general [58], not only addictive behaviors related to pharmacological agents. a pilot study by grant et al. [59] investigated the efficacy of nac in the treatment of pathological gambling. twenty-seven pathological gamblers were administered nac over an 8 week period in an open-label design, start- ing with an initial dose of 600 mg/day that was titrated up over the first 4 weeks until a noticeable clinical improvement was seen, with a maximum possible dose being 1800 mg/day. the yale-brown obsessive compulsive scale modified for pathological gam- bling (pg-ybocs) was used as the primary endpoint. pg-ybocs scores were found to be significantly decreased by the end of the 8 weeks, with a mean effective nac dose of 1476.9 ± 311.13 mg/day. sixteen participants were classified as responders, defined by a 30% or greater reduction in pg-ybocs score. of these, 13 participants entered a double-blind follow-up phase, where they were randomized to either con- tinue receiving their maximum dose from the open-label phase versus placebo over a 6 week period. at the end of the double-blind phase, 83.3% of the nac group still met responder criteria in comparison to only 28.6% of those assigned to placebo. although the first of its kind, this well-designed pilot study provides preliminary data in support of the efficacy of nac in the treatment of pathological gambling. a longer-term study by bernardo et al. [60] investigating the effect of 2 g/day nac on the use of alcohol, tobacco, and caffeine use in patients with bipolar disorder failed to find efficacy for nac. seventy-five participants were randomized to nac or pla- cebo over a 6 month period, with no significant changes in substance use observed over the length of the trial, with the exception of reduced caffeine intake in the nac group at week 2. however, it is important to note that patients were selected for the study on the basis of clinical criteria for bipolar disorder, rather than a primary substance abuse disorder. for this reason, there were low rates of substance use in the cohort, which detracted from the statistical power necessary to determine a treatment effect. increasing glutathione production in schizophrenia and bipolar disorder csf levels of gsh have been found to be decreased by 27% in drug-naive schizo- phrenia patients, while mrs has revealed that levels in the medial pfc are reduced by as much as 52% [61]. decreased levels of gsh have also been reported in the cau- date region in schizophrenia patients, as revealed by post-mortem assay [62]. there is evidence to suggest that decreased levels of gsh in schizophrenia are due to genetic polymorphisms in the genes responsible for gsh synthesis [63,64]. due to the effi- cacy of nac in boosting gsh levels in the cns, it has been investigated for pos- sible clinical benefits in the treatment of schizophrenia. berk et al. [65] administered nac 2000 mg/day versus placebo over a 6 month period to 140 patients with chronic schizophrenia, as augmentation to their regular antipsychotic medication. patients receiving nac were found to have a significant reduction in negative symptoms of schizophrenia as measured by the positive and negative symptoms scale (pnss) as |
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28 | neurocognition and micronutrients in the elderly age-related neurocognitive changes even in healthy elderly, changes in cognition occur across the life span, with memory decline widely held to be one of the hallmarks of advanced age. decline occurs to processes that rely on complex, controlled, goal-oriented behavior, including per- formance monitoring, the generation of future goals, and the ability to adjust behav- ior in response to feedback (budson and price, 2005). these cognitive operations are referred to as executive function and are particularly important for effective working memory and episodic memory performance. in comparison, other more declarative forms of memory including vocabulary and verbal iq remain relatively intact in older adults (christensen, 2001). crystallized intelligence, described as knowledge gained from cultural influences and experience tends to increase until age 60, rather than decrease with age (jones and conrad, 1933). beyond the age of 70, crystallized abilities decline, albeit to a lesser degree than fluid intelligence (christensen et al., 1994). disruptions in the frontal–striatal system and medial temporal cortical regions are thought to contribute to decline in executive function over the life span (buckner, 2004). evidence from the field of neuroimaging has corroborated these findings, demonstrating age-related changes in frontal neural activity during epi- sodic memory, semantic memory, and working memory activation tasks (cabeza, 2002; phillips and andrés, 2010). loss of brain volume can occur as neurons become more susceptible to the effects of mitochondrial dysfunction, changes in metabolic rate, oxidative stress, and neuroinflammation (floyd and hensley, 2002). this decrease in brain volume exerts effects upon cognitive function, with age-related atrophy shown to be a predictor of cognitive decline on iq measures (rabbit et al., 2008). volumetric imaging studies indicate that the frontal white matter is preferentially vulnerable to aging (raz et al., 2005; firbank et al., 2007). small infarcts induce anterior white-matter deterioration (pugh and lipsitz, 2002), which in turn may decrease the efficiency of frontally mediated executive pro- cesses (buckner, 2005). longitudinal studies have shown that cognitive change in healthy elderly is not a unitary process and that advancing age is accompanied by greater interindi- vidual variance, particularly in the domains of memory (rabbitt et al., 2004) and cognitive speed (christensen, 2001; wilson et al., 2004). the diversity of these trajectories indicates that cognitive aging does not occur at the same rate for all individuals and some will experience greater decline than others. individual dif- ferences stemming from genetic risk factors (alexander et al., 2007), education (ardila et al., 2000), cardiovascular function (beeri et al., 2009), physical activity (larson et al., 2006), depression (depp and jeste, 2006), and nutritional status (moreiras et al., 2007) represent a few of the more widely researched predictors of cognitive decline in the elderly. in some cases, poorer memory performers may be in the prodromal stage of an age-related neurodegenerative disease such as ad as many of the same cognitive domains to be affected by the normal aging pro- cess are exacerbated in ad (collie and maruff, 2000). ad is the most common form of dementia in the elderly and is characterized by the dsm-iv as a marked decline from previous functioning in short-term memory and a severe disruption |
29 | natural medicines, nutraceuticals and neurocognition occur, causing an intracellular accumulation of homocysteine, which may be toxic to neurons or lead to amyloid and tau protein accumulation (obeid and herrmann, 2006). hyperhomocysteinemia may also induce gene expression in the brain and interact with specific neural targets including cellular receptors, intracellular pro- teins, and molecules of nitric oxide, leading to neuropathology (mccaddon, 2006). vitamin b deficiency may exert more direct effects on cognitive function via the role of these vitamins in the production of neurotransmitters in the brain. in order to maintain normal levels of homocysteine, vitamin b6, b12, and folic acid are required in the methylation of homocysteine to methionine. the amino acid methionine is essential to one-carbon metabolism, a series of biological processes crucial for dna synthesis, dna repair, and various methylation reactions (mattson and shea, 2003). in the central nervous system, methionine is required in the syn- thesis of s-adenosylmethionine (sam), the sole donor for methylation reactions in the brain. the neurotransmitters dopamine, norepinephrine, and serotonin, as well as proteins, phospholipids, dna, and myelin, are the products of these reactions (selhub et al., 2000). additionally, sam is essential for maintenance of choline in the cns as well as the production of acetylcholine and the antioxidant glutathione (tchantchou et al., 2008). in accordance with the hypomethylation hypothesis, some loss of cognitive function in the elderly may be the end result of a lower produc- tion of sam and consequently neurotransmitters due to b12 and folate deficiency (calvaresi and bryan, 2001). a second hypothesis has proposed that impaired neurocognitive function in the elderly may stem from the injurious effects of elevated levels of homocysteine (calvaresi and bryan, 2001). in the brain, elevated homocysteine increases oxidative stress and dna damage, triggers apoptosis, and imparts excitotoxic effects (sachdev, 2005). in vitro, homocysteine disrupts neuronal homeostasis by multiple routes including n-methly-d-aspartate (nmda) channel activation leading to excessive calcium influx and glutamate excitotoxicity (ho et al., 2002). hyperhomocysteinemia may also induce gene expression and interact with specific targets including cellular receptors, intracellular proteins, and molecules of nitric oxide, leading to neuropa- thology (mccaddon, 2006). elevated homocysteine also exerts a detrimental effect on the cardiovascu- lar system via pro-coagulant actions toward platelets and vascular endothelium (de koning et al., 2003). vascular damage may be related to reduced bioavailability of endothelial nitric oxide, which is a powerful vasodilator (obeid and herrmann, 2006). furthermore, homocysteine-induced damage to endothelial cells promotes arteriosclerosis, which is in turn associated with poorer cognitive function (breteler et al., 1994; knopman et al., 2001; seshadri, 2006). collectively these findings sug- gest homocysteine may affect cognitive function in the elderly, via direct effects on the brain or through indirect mechanisms operating on the cardiovascular system. antioxidants and oxidative stress it is thought that free radicals and oxidative stress contribute to the neuronal changes responsible for cognitive decline in normal and pathological aging. oxidative stress represents a disturbance in the equilibrium status of prooxidant reactions involving |
30 | neurocognition and micronutrients in the elderly oxygen free radicals and those involving antioxidants (valko et al., 2007). it is the maintenance of this prooxidant/antioxidant balance via redox homeostasis that is vital for healthy cellular function. vitamin a, c, e, selenium, and coenzyme q10 possess potent antioxidant actions and protect neural tissue from aggression by free radicals (bourre, 2006). beta-carotene is a precursor to vitamin a and is a powerful antioxidant. vitamin c is known to interact synergistically with b complex vitamins and is essential for the metabolism and utilization of folic acid (huskisson et al., 2007). vitamin c levels are particularly high in the brain and this antioxidant is also necessary for the production of some neurotransmitters and the transforma- tion of dopamine into noradrenalin (bourre, 2006). vitamin e is a lipid soluble chain-breaking antioxidant, which exercises neuroprotective effects against reactive oxygen species injuries (cantuti-castelvetri et al., 2000). vitamin e interacts syner- gistically with selenium possibly increasing the antioxidant capacity of this vitamin (bourre, 2006). coenzyme q10 is also a lipid soluble molecule that acts as an anti- oxidant and coenzyme for mitochondrial enzymes (boreková et al., 2008). according to the free radical hypothesis of aging, detrimental age-related changes take place in the brain as the result of an inability to cope with oxidative stress that occurs throughout the life span (beckman and ames, 1998). oxidative stress can be defined as an excessive bioavailability of reactive oxygen species (ros) caused by an imbalance between production of ros and destruction of ros by antioxi- dants (kregel and zhang, 2007). ros are produced in the mitochondria in aero- bic cells and cause damage to mitochondrial components and initiate degradative processes including damage to lipids, proteins, and dna (floyd and carney, 1992; cadenas and davies, 2000). in particular, the brain is vulnerable to the effects of oxidative stress as it possesses reduced free radical scavenging ability and requires large quantities of oxygen (floyd and carney, 1992; cantuti-castelvetri et al., 2000). in the body, oxidative stress can lead to lipid peroxidation, a deleterious process that modifies the fluidity and permeability of neuronal membranes leading to an altera- tion of cellular functioning and damaged membrane bound receptors and enzymes (mariani et al., 2005). vitamin e exerts antioxidant activity in cell membranes and can inhibit lipid peroxidation (isaac et al., 2008). vitamins c and e have been dem- onstrated to decrease oxidative dna damage markers (boothby and doering, 2005). markers of oxidative stress were reduced, including high sensitivity c reactive pro- tein, ldl oxidation f2-isoprostanes, and monocyte superoxide anion concentrations following supplementation with vitamin e for a period of 2 years (devaraj et al., 2007). subsequently, neuroprotective effects of antioxidants against oxidative dam- age in the brain may represent a mechanism that can enhance cognition or delay the rate of cognitive decline in the elderly. in older adults, low intake and peripheral levels of antioxidants appear to be asso- ciated with greater risk of vascular disease (jialal and devaraj, 2003). oxidative stress has been further implicated in the pathophysiological process of cardiovascu- lar disease and stroke (mariani et al., 2005). throughout the progression of cardio- vascular disease, low density lipoprotein (ldl) accumulates in the sub-endothelial space in arteries where it becomes oxidized leading to foam cell formation, endo- thelial dysfunction and injury, and generation of atherosclerotic lesions (diaz et al., 1997). cellular antioxidants protect against the cytotoxic effects of oxidized ldl, |
31 | neurocognition and micronutrients in the elderly been administered together with, at minimum, a verbal memory and verbal fluency assessment of executive function. as a separate entity from cognitive performance, cognitive decline has also been investigated using these instruments, not withstand- ing that decline can only be measured longitudinally. b vitamins vitamin b12 depletion is common in old age (wolters et al., 2003). the effects of atrophic gastritis are thought to contribute to insufficient b12 absorption in the elderly, rather than a lack of the micronutrient in the diet per se (selhub et al., 2000). observations of psychiatric symptoms associated with b12 deficiency have been documented since 1849 and over the past 50 years low b12 status has been related to memory impairment, personality change, and psychosis (mccaddon, 2006), many of which overlap with dementia (american psychiatric association, 2000). more recent evidence has shown that folate and homocysteine are equally impor- tant for mental function. interestingly relationships between mci and low serum folate levels (quadri et al., 2004) and elevated plasma total homocysteine have been reported (quadri et al., 2005). based on these findings, the authors of these studies proposed that low folate and elevated homocysteine may predate dementia onset and that maintenance of micronutrient levels through dietary supplementation may aid in dementia prevention. while this is a promising assertion, it is still under debate as to whether deficient b12 and folate may contribute to the neurodegenerative process associated with ad, or whether deficiencies may reflect a consequence of the disease process (seshadri, 2006). numerous studies have also investigated the association between b vitamins, homocysteine and cognitive function in healthy elderly. in the cross-sectional, maine- syracuse study of 812 young through to elderly subjects, a relationship was identified between vitamin b6 and multiple cognitive domains encompassing visual–spatial organization, working memory, scanning-tracking, and abstract reasoning (elias et al., 2006). outcomes from the third national health and nutrition examination survey revealed that individuals aged over 60 years, with elevated homocysteine accompanied by low folate levels, demonstrated poorer story recall than those with normal levels of homocysteine (morris et al., 2001). findings from the singapore longitudinal ageing study, which investigated 451 high functioning chinese elders, revealed that higher levels of folate were associated with better scores on a verbal learning instrument (feng et al., 2006). a study by riggs et al. (1996) revealed that middle aged to elderly men from the boston veterans affairs normative aging study who had higher concentrations of plasma homocysteine and low concentrations of b12 and folate also displayed poorer spatial copying skills. follow-up analysis from this study revealed that plasma folate became the strongest predictor of spatial copy- ing ability, independent of homocysteine, 3 years later (tucker et al., 2005). other trials have examined the relationship between b vitamins or homocysteine and cognition using a longitudinal design. findings from the macarthur studies of successful aging showed that low folate levels in individuals aged in their 70s were predictive of cognitive decline 7 years later (kado et al. 2005). it was found by nurk et al. (2005) that elevated homocysteine at baseline predicted memory deficit after |
32 | natural medicines, nutraceuticals and neurocognition 6 years in those aged 65–67 who took part in the hordaland homocysteine study. although a historical connection between b12 and cognition has been established, several epidemiological studies have failed to find an association between b12 con- centration and cognitive status (kado et al., 2005; mooijaart et al., 2005; nurk et al., 2005; feng et al., 2006). alternatively, measurement of methylmalonic acid (mma), a product of amino acid metabolism, may provide a more useful diagnostic tool for b12 deficiency (moretti et al., 2004). results from the oxford healthy aging project showed that when holotranscobalamin (holotc), the biologically active fraction of vitamin b12, and mma were used as measures of vitamin b12 status, each were asso- ciated with a more rapid cognitive decline on the mmse over 10 years (clarke et al., 2007). when considered together, outcomes from these longitudinal studies point to a more causal role of b12 and folate deficiency in cognitive decline. antioxidant vitamins antioxidant vitamin status in the blood has been associated with cognitive func- tion in the elderly. the third national health and nutrition examination survey investigated blood vitamin levels taken from a multiethnic sample of 4809 elderly residents of the united states (perkins et al., 1999). findings from this trial revealed that higher serum levels of vitamin e were associated with better memory recall of a three sentence story. interestingly, no correlations between vitamin a, beta-carotene, selenium, or vitamin c with memory performance were identified. by contrast, in a sample of swiss elderly aged 64–95 years, both past and current levels of ascorbic acid and beta-carotene were associated with free recall, recognition, and vocabu- lary performance (perrig et al., 1997). in the cognitive change in women study, a comprehensive neuropsychological test battery was utilized to assess the domains of memory, executive function, language, attention, and visual function in 526 women aged 60 or above with cognitive impairment (dunn et al., 2007). baseline results from this study revealed that low serum alpha-tocopherol status was cross section- ally associated with increased odds ratio of memory and mixed cognitive impair- ments. in contrast, previous vitamin e supplement intake was not associated with any type of cognitive impairment. intake of antioxidant vitamins from the diet has also been linked to cognitive function in older adults. the chicago health and aging project investigated the dietary habits of 2889 community residents, aged 65–102 using a food frequency questionnaire (morris et al., 2002). the results of this study revealed that higher intake of vitamin e from the diet or from supplements was associated with a slower rate of cognitive decline over 3 years as measured by a combined cognitive score derived from tests of immediate and delayed story recall, a measure of perceptual speed and the mmse. in contrast, findings from the rotterdam study revealed that intake of beta-carotene, and not vitamin c or e, was associated with performance on the mmse in elderly aged 55–95 years (warsama jama et al., 1996). use of vitamin e and c supplements by elderly men has been linked to better cognitive function at follow up 3–5 years later (masaki et al., 2000). results from the cache county study revealed that participants aged 65 years or older who had a lower a intake of vitamin c, vitamin e, and carotene also had a greater acceleration |
33 | neurocognition and micronutrients in the elderly of the rate of cognitive decline on the 3ms over 7 years compared to those with a higher use. the conclusions from this study were that higher antioxidant dietary vita- min c, vitamin e, and carotene may delay cognitive decline in the elderly (wengreen et al., 2007). separate analyses from the same trial demonstrated that those with the apoe e4 allele using vitamin c, e, or multivitamin supplements in combination with nonsteroidal anti-inflammatory drugs showed less cognitive decline over an 8 year period than those with the e4 allele who were taking antioxidant supplements (fotuhi et al., 2008). it was suggested from these results that those at a higher genetic risk of developing ad may benefit from use of anti-inflammatories and antioxidant supplementation. thus, the use of combined vitamin c and e supplements appears to influence cognition in the elderly. long-term consumption (>10 years) of vitamin c and e supplements was associated with better performance on cognitive tests includ- ing verbal fluency, digit span backward, and a telephone administered version of the mmse, in a large sample of community-dwelling elderly women who participated in the nurse’s health study (grodstein, 2003). women taking both supplements displayed equivalent cognitive function to individuals 2 years younger. similarly, elderly subjects from the canadian study of health and ageing using combined vitamin c and e and supplements were less likely to experience significant cognitive decline on the 3ms after 5 years (maxwell et al., 2005). collectively, results from these studies suggest that chronic use of antioxidant supplements may help slow the rate of cognitive decline in the elderly. zinc few studies have investigated the relationship between zinc and cognition in older adults. in older adults recruited from european countries including italy, greece, germany, france, and poland, plasma zinc status was correlated with global cogni- tive functioning as measured by the mmse (marecllini et al., 2006). the observation that inhabitants from countries with diets rich in zinc exhibited superior cognitive function suggests that zinc supplementation may have beneficial effects on cognition in elderly who are deficient. vitamin d in a large sample of middle aged to elderly men free from dementia, levels of vita- min d have been associated with digit symbol substitution performance (lee et al., 2009). findings from the nutrition and memory in elders study revealed a posi- tive correlation between levels of vitamin d and measures of executive function and attention processing speed in over 1000 elderly subjects (buell et al., 2009). as this relationship remained robust after adjustment for a number of factors including homocysteine, apoe4 allele, plasma b vitamins, and multivitamin use, it is possible that vitamin d may also represent an important predictor of cognitive function in the elderly. in a sample of elderly french community-dwelling women, dietary intake of vitamin d, as estimated from a food frequency questionnaire, has been associated with performance on a global cognitive measure (annweiler et al., 2010), indicating intake of vitamin d may also be important for cognition. |
34 | natural medicines, nutraceuticals and neurocognition in summary, the findings from population studies have demonstrated that in the elderly cognitive function is related to dietary intake, long-term supplement use, and circulating levels of individual vitamins. the results from these studies indicate that dietary intake of b vitamins, antioxidants, and selected minerals may comprise important predictors of cognitive function, particularly as individuals enter the later stages of the life span. vitamin status and brain structural correlates in the elderly when considering the neurocognitive effects of dietary factors, it may be useful to examine the association between vitamin status and brain structural parameters. most commonly structural mri has been used for this purpose, with more com- prehensive examinations undertaken at post mortem. in a fascinating study, blood nutrient levels were correlated with brain pathology in elderly nuns who lived in the same convent, ate at the same kitchen, and consequently had comparable environ- mental factors and overall lifestyle (snowdon et al., 2000). blood was collected and analyzed for nutrients, lipids, and nutrient markers. following the death of 30 elderly nuns, a neuropathologist examined the brains for signs of atrophy, ad lesions (neurofibrillary tangles, senile plaques, and neutritic plaques), and atherosclerosis in the major arteries at the base of the brain. the results demonstrated that serum folate levels were negatively related to atrophy of the neocortex, particularly in those with a significant number of ad lesions in the neocortex. it was proposed that the association between low folate levels and cortical atrophy may not be entirely due to the deleterious effects of vascular disease, as folate was negatively correlated with subgroups of participants with minimal signs of vascular neuropathology such as arteriosclerosis and brain infarcts. similarly, de lau et al. (2009) have posited that neuropathology related to low b12 levels may arise from other nonvascular factors. the larger-scale, population-based, rotterdam scan study provided evidence that poorer vitamin b12 status in the normal range was significantly associated with greater severity of white-matter lesions, in particular periventricular white-matter lesions in healthy elderly. however, as b12 levels were not related to cerebral infarcts, these researchers hypothesized that the association between b12 levels and white- matter lesions may due to effects on myelin integrity in the brain, rather than through vascular mechanisms alone. vitamin b12 levels in healthy community-dwelling elderly have also been associ- ated with brain volume loss over a 5 year period (vogiatzoglou et al., 2008). the results of this study revealed that the decrease in brain volume was greater among those with lower vitamin b12 and holotc levels. specifically, those in the bottom ter- tile for b12 (<308 pmol/l) at baseline experienced the greatest rate of brain-volume loss. based on these findings, the authors concluded that plasma vitamin b12 status may provide an early marker of brain atrophy and consequently may represent a potentially modifiable risk factor for cognitive decline in the elderly. findings from a recent randomized trial indicated that 2 years b vitamin supplementation was capable of slowing the rate of brain atrophy (smith et al., 2010). in this study elderly with mci were assigned to a treatment of combined vitamins b6, b12, and folate |
35 | natural medicines, nutraceuticals and neurocognition of 3 years. the results revealed that the folic acid treatment led to an improvement in information processing speed that was not evident for the placebo treatment. benefits were also found for a composite score that included measures of information pro- cessing speed and memory. other less positive outcomes have been reported. eussen et al. (2006) failed to identify any effects of b12 or combined b12 and folate supplementation on cognition in older persons with mild vitamin deficiency aged 70 or above. in this trial, partici- pants allocated to either 1000 μg b12 alone or 1000 μg b12 combined with 400 μg folate daily for 24 weeks did not show any improvements on a battery of neuropsy- chological tests. comparably a 4 month study into the effects of 4 months combined vitamin b16, b12, and folate supplementation in community-dwelling elderly did not identify any treatment-related improvements to neuropsychological task perfor- mance (lewerin et al., 2005). in a cross-sectional study of young, middle aged, and older women, mixed results were uncovered regarding b6, b12, and folate supple- mentation (bryan et al., 2002). while memory performance improved for the oldest group who received folate, participants supplemented with b12 or folate performed worse on a verbal fluency task than those who received b6 or the placebo. the short treatment period coupled with the low dose of b12 used in this study (15 μg) may account for these results. on the basis of the findings of bryan et al. (2002) that the oldest participants demonstrated cognitive improvements with folate supplementation, it could be argued that the treatment effects of b vitamins may be specific to certain sub- groups amongst the elderly, such as the very old or those with cognitive impairment. support for this premise has been obtained from a study of patients with depleted vitamin b12 levels at baseline (eastley et al., 2000). in this trial, 3 months inter- vention improved verbal fluency for individuals with cognitive impairment, while the same benefits were not observed for those with established dementia. several smaller trials have demonstrated minor improvements to memory in individuals at risk of cognitive decline due to low vitamin status. for example, deijen et al. (1992) identified improvements to long-term memory in vitamin b6 deficient men, aged in their 70s following 3 months vitamin b6 supplementation. it should be noted, how- ever, that this effect could be partially attributed to a decrease in performance of the placebo group over this time period. memory improvements were also observed in a small trial of elderly aged 70–90 years with low folate at baseline when treated for deficiency for a period of 2 months (fioravanti et al., 1997). however, a trial in patients with ischemic vascular disease did not reveal any cognitive improvements to a letter digit coding test or a telephone interview of cognitive status following 12 months treatment with either folate and vitamin b12 or vitamin b6 and riboflavin (stott et al., 2005). a cochrane review conducted by malouf and grimley evans (2008) indicated that there was not sufficient evidence to conclude that folate administered in isolation or combined with vitamin b12 improved cognition in the elderly. based on a system- atic review of randomized controlled trials, balk et al. (2007) concluded that there was little beneficial effect of b12, b6, or folate supplementation on cognitive function and that there is still a need for longer, larger powered studies to accurately assess whether vitamin b vitamin supplementation is effective to slow cognitive decline |
36 | neurocognition and micronutrients in the elderly or improve cognitive performance in the elderly. on the basis of their review, balk et al. (2007) further articulated that only cognitive tests that adequately differentiate individual cognitive domains should be used to evaluate the efficacy of b vitamin supplementation. in summary, evidence from intervention studies suggests that supplementation with vitamin b12 or folate may provide only limited improvements to processing speed and memory in the elderly. antioxidant vitamins the effects of selected antioxidant supplementation on cognitive measures in elderly adults have been investigated in several large-scale placebo-controlled stud- ies. within some of these studies the primary aim was not to measure cognitive performance changes with supplementation and in some studies no cognitive data was available prior to supplementation. participants in the age-related eye disease study were randomly assigned to receive daily antioxidants (vitamin c, 500 mg; vitamin e, 400 iu; beta-carotene, 15 mg), zinc and copper (zinc, 80 mg; cupric oxide, 2 mg), antioxidants plus zinc and copper, or placebo. after approximately 7 years, there was no difference between the treatment groups on any of the cog- nitive tests (yaffe et al., 2004). a cognitive testing component including assess- ment of general cognition, verbal memory, and category fluency was added to the physician’s health study, where elderly men supplemented their diet with 50 mg beta-carotene or a placebo on alternate days (grodstein et al., 2007). there was no impact of treatment with beta-carotene for 3 years or less on cognitive performance, whereas treatment duration of at least 15 years provided significant benefits for ver- bal memory, cognitive status, and a composite of these measures. these findings indicate that long-term interventions, implemented at early stages of brain aging may provide cognitive benefits. using the same outcome measures, subjects in the women’s health study received vitamin e supplementation (600 iu) on alternate days or placebo (kang et al., 2006). the results of this study showed no effect of the treatment on a global composite score after 9 1 2 years and it was concluded that long-term use of vitamin e supplements did not provide cognitive benefits among generally healthy older women. in brief, there appears to be some advantage to long-term beta-carotene supple- mentation in the elderly; however, the mainly telephone-administered cognitive tests used in these trials may not be sensitive to the neurocognitive effects of antioxidant supplementation. zinc fewer studies have utilized rct methodology to explicitly evaluate the cogni- tive effects of trace minerals such as zinc. in a trial of healthy adults aged 55–87 years, subjects received either 15 or 30 mg of zinc per day (maylor et al., 2006). treatment effects were assessed at 3 and 6 months using measures of visual mem- ory, working memory, attention, and reaction time from the cambridge automated neuropsychological test battery. at the 3 month testing period, spatial working |
37 | neurocognition and micronutrients in the elderly unequal treatment group sizes, there appeared to be some memory enhancements associated with the multivitamin and poly-herbal treatments (shah and goyal, 2010). replication of this study with larger, equal group sizes may be required to confirm these results. in a trial of young to elderly subjects, improved performance on a digit memory task and the trails making test have been documented after time periods of 2 weeks and 3 months treatment with a dietary supplement consisting of folic acid, b12, vitamin e, s-adenosylmethionine, n-acetylcysteine, and acetyl-l-carnitine (chan et al., 2009). interestingly, in an open label extension, memory benefits were diminished when the treatment was withdrawn for 3 months and reemerged when treatment was reinstated for a further 3 months. as only a subset of elderly subjects were shown to respond to the treatment, and only a fraction of the initial sample remained at the 12 month conclusion of this study, replication of this study may be necessary. investigations in younger subject groups have also identified cognitive improve- ments following multivitamin supplementation. after 12 months supplementation with a multivitamin, benefits to speed of attention has been observed, although improvements were restricted to female participants (benton et al., 1995). the results from other trials indicate that the cognitive benefits of multivitamin supplementation in young adults may be limited to measures that require high levels of cognitive demand. in a 9 week study of young to middle aged females, multivitamin-related cognitive enhancements were observed on a computerized multitasking framework consisting of mathematical, stroop, numerical processing, and memory search tasks (haskell et al., 2010). similarly cognitive performance has been augmented on a highly demanding serial subtraction task following 33 days multivitamin supplemen- tation in men of a comparable age range (kennedy et al., 2010). when considered together, these findings indicate that cognitive benefits of multivitamin supplementa- tion may not only be restricted to the elderly. limitations and future directions despite relatively promising findings that have linked blood levels of vitamins and long-term antioxidant use to better cognitive function in the elderly, the translation of this evidence to randomized controlled investigations into the effects of dietary vitamin supplementation on cognition has been less positive. a meta-analysis of ran- domized controlled trials has concluded that b vitamins, antioxidants, and multi- vitamins do not exert clinically important effects on global cognition in the elderly (jia et al., 2008). due to methodological differences pertaining to the specific ingre- dients, vitamin concentrations, and cognitive instruments, it is difficult to formulate cross-study comparisons of the efficacy of vitamin use for this purpose. in order to obtain clear evidence that dietary supplementation with micronutrients can improve cognitive performance or slow the rate of cognitive decline in the elderly, there needs to be greater forethought and justification of the cognitive domains under investiga- tion in randomized controlled trials. for instance, global measures such as the mmse do not refer to any specific cognitive domains and provide only an overall estimate of an individual’s level of functioning. the use of such measures may result in difficulty distinguishing the |
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44 | natural medicines, nutraceuticals and neurocognition alzheimer’s disease (ad) alzheimer’s disease (ad) is a progressive neurodegenerative brain disorder that gradually destroys a patient’s memory and ability to learn, make judgments, com- municate effectively, and perform day-to-day tasks. the short-term memory is affected first, caused by neuronal dysfunction and degeneration in the hippocampus and amygdala. as the disease progresses further, neurons also degenerate and die in other cortical regions of the brain (stuchbury and münch, 2005). sufferers then often experience dramatic changes in personality and behavior, such as anxiety, paranoia, or agitation, as well as delusions or hallucinations (cummings, 2004). the prevalence of ad in the age bracket of 65–69 years is 1%; 70–74 years, 3%; 75–79 years, 6%; 80–84 years, 12%, and for people aged 85 and over the prevalence is 25%. ad is further characterized by two major neuropathological hallmarks. the depo- sition of neuritic, β-amyloid (aβ) peptide-containing senile plaques in hippocampal and cerebral cortical regions of ad patients is accompanied by the presence of intracellular neurofibrillary tangles that occupy most of the cytoplasm of pyramidal neurons. inflammation, as evidenced by the activation of microglia and astroglia, is another hallmark of ad. inflammation, including superoxide production (“oxidative burst”), is a significant source of oxidative stress in ad patients (münch et al., 1998; retz et al., 1998). the inflammatory process occurs mainly around the amy- loid plaques and is characterized by pro-inflammatory substances that are released from activated microglia and astroglia (wong et al., 2001b). cytokines, including interleukin(il)-1β, il-6, macrophage colony-stimulating factor (m-csf), and tumor necrosis factor (tnf-α), are the prominent signaling molecules in the inflammatory process, being responsible for a vicious cycle of microglial and astroglial activation, resulting in the secretion of neurotoxins including superoxide and nitric oxide (griffin et al., 1995). in addition to those morphological and physiological alterations, ad is also associated with a markedly impaired cerebral glucose metabolism as detected by reduced cortical [18f]-deoxyglucose utilization in positron emission tomography (ishii and minoshima, 2005). cholinergic deficit in ad ad patients show a progressive neuronal cell loss that is associated with region- specific brain atrophy. in particular, the earliest and most severely affected pathway is the cholinergic projection from the nucleus basalis of meynert to areas of the cerebral cortex (nordberg et al., 1987). loss of basal forebrain cholinergic neurons is dem- onstrated by a reduction in the expression of choline acetyltransferase (chat), lower numbers of muscarinic and nicotinic acetylcholine receptors, and lower levels of acetylcholine (ach) itself (nordberg and winblad, 1986). these changes are highly correlated with the degree of dementia in ad. ach is derived from acetyl-coa, the final product of the glycolytic pathway. pyruvate, derived from glycolytic metabo- lism serves as an important energy source in neurons. therefore, the inhibition of pyruvate production, for example, by glucose depletion, is considered a crucial factor that leads to acetyl-coa deficiency in ad brains. ach is hydrolyzed by acetylcho- line esterase (ache) and since ad patients have reduced levels of chat and ach, |
45 | natural medicines, nutraceuticals and neurocognition purified chat (from rabbit bladder, rat brain, and heart extracts) causes complete disappearance of enzyme activity. the addition of dhla restored activity toward normal levels while the addition of reduced ascorbic acid or reduced nicotinamide adenine dinucleotide was not effective (haugaard and levin, 2002). the authors concluded that dhla serves an essential function in the action of this enzyme and that the ratio of reduced to oxidized la plays an important role in ach synthesis. from these data the authors further conclude that dhla (1) may act as a coenzyme in the chat reaction or (2) is able to reduce an essential functional cysteine residue in chat, which cannot be reduced by any other physiological antioxidant, including reduced gsh (haugaard and levin, 2002). la: a potent metal chelator there is now compelling evidence that aβ, the main component of amyloid plaques in the ad-affected brain, does not spontaneously aggregate as was originally thought. evidence suggests that there is an age-dependent reaction with excess metal ions in the brain (copper, iron, and zinc), which induces the peptide to precipitate and form plaques. furthermore, the abnormal combination of aβ with copper or iron ions induces the production of hydrogen peroxide from molecular oxygen (huang et al., 1999), which subsequently produces the neurotoxic hydroxyl radical by fenton or haber–weiss reactions. because la is a potent chelator of divalent metal ions in vitro, the effect of an rla inclusive diet on cortical iron levels and antioxidant status was investigated in aged rats (suh et al., 2005). results show that cerebral iron levels in old la-fed animals were lower when compared to controls and were similar to levels seen in young rats. these results thus show that chronic la supplementation may be a means to modulate the age-related accumulation of cortical iron content, thereby low- ering oxidative stress associated with aging (suh et al., 2005). since amyloid aggre- gates have been shown to be stabilized by transition metals such as iron and copper, it was also speculated that la could inhibit aggregate formation or potentially dissolve existing amyloid deposits. fonte et al. successfully resolubilized aβ with transition metal ion chelators and showed that la enhanced the extraction of aβ from the fron- tal cortex in a mouse model of ad, suggesting that like other metal chelators, it could reduce amyloid burden in ad patients (fonte et al., 2001). a potential side effect of a long-term therapy with high doses of a metal chelator such as la could be the inhibi- tion of metal containing enzymes such as insulin degrading enzyme or superoxide dismutase. suh et al. investigated whether la and dhla remove copper or iron from the active sites of cu, zn superoxide dismutase, and aconitase. they found that even at millimolar concentrations neither la nor dhla altered the activity of these enzymes (suh et al., 2004b), providing promising results for the long-term use of la in ad. la: an anti-inflammatory antioxidant and modulator of redox-sensitive signaling ad is accompanied by a chronic inflammatory process around amyloid plaques, characterized by the activation of microglia and astrocytes and increased levels of radicals and pro-inflammatory molecules such as inos, il-1 β, il-6, and tnf-α |
46 | lipoic acid as an anti-inflammatory and neuroprotective treatment (griffin et al., 1995). ad patients also show increased cytokine levels (e.g., il-1 β and tnf-α) in the cerebral spinal fluid (csf), with tnf-α being a good predictor for the progression from mild cognitive impairment to ad. recently, much attention has been paid to ros as mediators in signaling processes, termed “redox-sensitive signal transduction.” ros modulate the activity of cytoplasmic signal transducing enzymes by at least two different mechanisms: oxidation of cysteine residues or reaction with iron–sulfur clusters. one widely investigated sensor protein is the p21ras protein (lander et al., 1997). activation of ras by oxidants is caused by oxi- dative modification of a specific cysteine residue (cys118). ras interacts with pi3- kinase, protein kinase c, diacylglycerol kinase, and map-kinase-kinase-kinase, regulating expression of il-1 β, il-6, and inos. la can scavenge intracellular free radicals (acting as second messengers), downregulate pro-inflammatory redox- sensitive signal transduction processes including nf-κb translocation, and thus attenuate the release of more free radicals and cytotoxic cytokines (bierhaus et al., 1997; wong et al., 2001a). la: a carbonyl scavenger cellular and mitochondrial membranes contain a significant amount of ara- chidonic acid and linoleic acid, precursors of lipid peroxidation products 4-hydroxynonenal (hne) and acrolein that are extremely reactive. acrolein decreases pyruvate dehydrogenase (pdh) and α-ketoglutarate dehydrogenase (kgdh) activities by covalently binding to la, a component in both the pdh and kgdh complexes. acrolein, which is increased in ad brains, may be par- tially responsible for the dysfunction of mitochondria and loss of energy found in the ad-affected brain through its inhibition of pdh and kgdh activities, potentially contributing to neurodegeneration (pocernich and butterfield, 2003). in a further study, levels of lipid peroxidation, oxidized glutathione (gssg), and nonenzymatic antioxidants and the activities of mitochondrial enzymes were measured in liver and kidney mitochondria of young and aged rats before and after la supplementation. in both the liver and kidney, a decrease in the activi- ties of mitochondrial enzymes was observed in aged rats. la supplemented aged rats showed a decrease in the levels of lipid peroxidation and inhibition of the activities of mitochondrial enzymes like isocitrate dehydrogenase, kgdh, suc- cinate dehydrogenase, nadh dehydrogenase, and cytochrome c oxidase. the authors conclude that la reverses the age-associated decline in mitochondrial enzymes and therefore may lower the increased risk of oxidative damage that occurs during aging (arivazhagan et al., 2001). la: a stimulator of glucose uptake and utilization (“insulinomimetic”) increased prevalence of insulin abnormalities and insulin resistance in ad may contribute to the disease pathophysiology and clinical symptoms. insulin and insulin receptors are densely but selectively expressed in the brain, including the medial temporal regions that support the formation of memory. it has recently been demonstrated that insulin-sensitive glucose transporters are localized to the |
47 | natural medicines, nutraceuticals and neurocognition same regions and that insulin plays a role in memory functions. collectively, these findings suggest that insulin contributes to normal cognitive functioning and that insulin abnormalities may exacerbate cognitive impairments, such as those asso- ciated with ad (watson and craft, 2003). this view is further supported by the finding that higher fasting plasma insulin levels and reduced csf: plasma insu- lin ratios (suggestive of insulin resistance) have also been observed in patients with ad. when ad patients were treated with insulin in a glucose clamp approach, a marked enhancement in memory was observed, whereas normal adults’ memory was unchanged (craft et al., 2003). as previously mentioned, ad is associated with a markedly impaired cerebral glucose metabolism in affected regions. impaired glucose uptake (partially mediated by insulin resistance) in vulnerable neuronal populations not only compromises production of ach but also renders neurons vulnerable to excitotoxicity and apoptosis. there is abundant evidence that la can ameliorate insulin resistance and impaired glucose metabolism in the periphery in type ii diabetes mellitus. one study examined the beneficial effects of la on glu- cose uptake using soleus muscles derived from nonobese, insulin-resistant type ii diabetic goto-kakizaki rats, a genetic rat model for human type ii diabetes. in this model, chronic administration of la moderately improved the diabetes-related deficit in glucose metabolism and protein oxidation, as well as the activation of akt/pkb and pi3k by insulin (bitar et al., 2004). in a further study, the incorpo- ration of 14c-2-deoxyglucose (2dg) into areas of basal ganglia was investigated in rats treated acutely or for 5 days with rla or sla. following acute adminis- tration, rla was more effective than sla in increasing 14c-2dg incorporation. for example, acute administration of rla caused an approximate 40% increase in 14c-2dg incorporation in the substantia nigra while sla was without effect. however, the effects observed were dependent on basal 14c-dg incorporation in different rat strains. following subacute administration, the pattern of change in 14c-2dg incorporation was altered and both isomers were equally effective. the effects of rla were largely maintained with increasing animal age, but the ability of the s-isomer to alter 14c-2dg incorporation was lost by 30 months of age. the authors conclude that rla has the ability to increase glucose utilization in vivo, which may be relevant to the treatment of neurodegenerative disorders (seaton et al., 1996). based on this and similar studies it is quite conceivable that la might increase glucose uptake in insulin-resistant neurons and thus provide more gly- colytic metabolites including acetyl-coa for these neurons. since ach synthesis depends on the availability of acetyl-coa provided from glucose metabolism, la might additionally be able to directly increase the concentration of the substrate acetyl-coa for ach synthesis (hoyer, 2003). upregulation of glutathione synthesis via activation of nrf-2 the tri-peptide γ-l-glutamyl-l-cysteinyl-glycine or glutathione (gsh) is the most abundant nonprotein thiol in animal cells. gsh is required for the maintenance of the thiol redox status of the cell, protection against oxidative damage, detoxification of endogenous and exogenous reactive metal ions and electrophiles, storage and transport of cysteine, as well as protein and dna synthesis, cell cycle regulation, |
48 | lipoic acid as an anti-inflammatory and neuroprotective treatment and cell differentiation (butterfield et al., 2002). gsh and gsh enzymes play a key role in protecting the cell against the effects of ros. the key functional ele- ment of gsh is the cysteinyl moiety, which provides the reactive thiol group. ros are reduced by gsh through the enzymatic activity of glutathione peroxidase (gsh-px) (butterfield et al., 2002). as a result, gsh is oxidized to gssg, which is rapidly reduced back to gsh by glutathione reductase (gr) at the expense of nadph. this is a redox-cycling mechanism to prevent gsh loss (pocernich et al., 2000). the key role of gsh is that it is a cofactor of glutathione peroxidase and glyoxalase i, important for the detoxification of ros and methylglyoxal, respec- tively. in the de novo synthesis, gsh is synthesized from its constituent amino acids by the sequential action of two enzymes, γ-glutamylcysteine synthetase (γ-gcs), which is the rate-limiting enzyme, and glutathione synthetase. γ-gcs catalyzes the formation of the dipeptide γ-glutamylcysteine, which is the rate-limiting substrate in this reaction. nuclear factor e2–related factor 2 (nrf2) is a transcription factor known to induce expression of a variety of cytoprotective and detoxification genes. in recent years, nrf2 has become a promising novel drug target. activators of nrf-2-mediated tran- scription increase the expression of enzymes involved in gsh synthesis, to main- tain sustainable high gsh production and provide protection to neurons against oxidative stress. nrf-2 activators (a class of potential gsh “boosters”) include tert- butylhydroquinone (tbh), sulforaphane (from broccoli), resveratrol, a variety of polyphenols, and α-lipoic acid (karelson et al., 2001). in 2002, it was suggested that lipoic acid, like the structurally related dithiolethi- ones, such as anethole dithiolethione (adt), induces phase ii detoxification enzymes (which are involved in conjugation reactions) in cultured astroglial cells. la, like adt, induced a highly significant, time and concentration dependent, increase in the activity of nad(p)h dehydrogenase (nqo1) and glutathione-s-transferase (gst) in c6 astroglial cells. the la- or adt-mediated induction of nqo1 was further confirmed by quantitative pcr and western blot analysis. this work for the first time unequivocally demonstrates la-mediated upregulation of phase ii detoxifica- tion enzymes, which may highly contribute to the neuroprotective potential of la. moreover, the data support the notion of a common mechanism of action of la and adt (flier et al., 2002). in 2004, hagen’s group at the linus pauling institute at oregon state university discovered that r-lipoic acid is an in vivo inducer of nrf2 and increases the enzymatic activity of gamma-glutamylcysteine ligase on a transcriptional level. they observed that the rate-controlling enzyme in gsh, gamma-glutamylcysteine ligase (gcl) loses enzymatic activity with age. with age, the expression of the catalytic (gclc) and modulatory (gclm) subunits of gcl decrease by about 50%. in addition, approximately 50% age-related loss in total and nuclear nrf2 levels was observed, suggesting attenuation of nrf2-dependent gene transcription. to determine whether the constitutive loss of nrf2 transcriptional activity also affects the inducible nature of nrf2 nuclear translocation, old rats were treated with rla. la administration increased nuclear nrf2 levels in old rats and induced nrf2 binding to the are and consequently, higher gclc levels and gcl activity were observed after la injec- tion (suh et al., 2004a). |
49 | natural medicines, nutraceuticals and neurocognition neuroprotective effects of la in vitro and in vivo protection of cultured neurons against toxicity of a𝛃, iron, and other neurotoxins by la aß, the major component of senile plaques, contributes to neuronal degeneration in ad by stimulating the formation of free radicals. zhang et al. have investigated the potential efficacy of la against cytotoxicity induced by aß (30 μm) and hydrogen peroxide (100 μm) in primary neurons of rat cerebral cortex and found that treat- ment with la protected cortical neurons against cytotoxicity induced by both toxins (zhang et al., 2001). in a similar study, lovell et al. investigated the effects of la and dhla on neuronal hippocampal cultures treated with aß (25–35) and iron/ hydrogen peroxide (fe/h2o2) (lovell et al., 2003). in a further study, müller and krieglstein tested whether pretreatment with la can protect cultured neurons against injury caused by cyanide, glutamate, or iron ions. neuroprotective effects were only significant when the pretreatment with la occurred for >24 h. the authors conclude that neuroprotection occurs only after pro- longed pretreatment with la and is probably due to the radical scavenger properties of endogenously formed dhla (muller and krieglstein, 1995). in summary, data from these studies suggest that pretreatment of neurons with la (or application of dhla) before exposure to aß or fe/h2o2 significantly reduces oxidative stress and increases cell survival. however, concomitant application of aß or fe/h2o2 with la can temporarily increase oxidative stress as the reduction of la by the pdh complex consumes reducing equivalents and inhibits energy production. protective effects of la against age-related cognitive deficits in aging rodents protective effects of la against cognitive deficits have been shown in several studies in aged rats and mice. in one study, a diet supplemented with rla was fed to aged rats to determine its efficacy in reversing the decline in metabolism seen with age. young (3–5 months) and aged (24–26 months) rats were fed for 2 weeks. ambulatory activity, a measure of general metabolic activity, was almost threefold lower in untreated old rats vs. controls, but this decline was reversed in old rats fed with rla (hagen et al., 1999). in a combination treatment study, the effects on cogni- tive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats a combination of acetyl-l-carnitine (alcar) and/or rla. dietary supplementation with alcar and/or rla improved memory, the combination being the most effective for tests of spatial memory and temporal memory. the authors suggest that feeding alcar and rla to old rats improves performance on memory tasks by lowering oxidative damage and improving mito- chondrial function. feeding the substrate alcar with rla restores the velocity of the reaction (k(m)) for alcar transferase and mitochondrial function. the prin- ciple appears to be that, with age, increased oxidative damage to protein causes a deformation of structure of key enzymes with a consequent lessening of affinity (k(m)) for the enzyme substrate (liu et al., 2002). |
50 | natural medicines, nutraceuticals and neurocognition egcg has previously been shown to prevent neuronal cell death caused by aβ neurotoxicity in cell cultures (choi et al., 2001; levites et al., 2003). a study by rezai-zadeh et al. (rezai-zadeh et al., 2005) reported that egcg reduced aβ gen- eration in vitro in neuronal-like cells and primary neuronal cultures from tg2576 mice, along with promotion of the nonamyloidogenic α-secretase proteolytic path- way. furthermore when 12 month old tg2576 mice were treated with 20 mg/kg egcg via intra-peritoneal injections for 60 days, it was found that aβ levels and plaque load in the brain were decreased. curcumin has been reported to be sev- eral times more potent than vitamin e as a free radical scavenger (zhao et al., 1989) and there is also increasing evidence showing that curcumin can inhibit aβ aggregation (yang et al., 2005). in a study by lim et al. curcumin was tested for its ability to inhibit the combined inflammatory and oxidative damage in tg2576 transgenic mice. in this study tg2576 mice aged 10 months old were fed a cur- cumin diet (160 ppm) for 6 months. their results showed that the curcumin diet significantly lowered the levels of oxidized proteins, il-1β, the astrocyte marker glial fibrillary acidic protein (gfap), soluble and insoluble aβ, and also plaque burden (lim et al., 2001). following on from this work, yang et al. evaluated the effect of feeding a curcumin diet (500 ppm) to 17 month old tg2576 mice for 6 months. when fed to the aged tg2576 mice with advanced amyloid accumu- lation, curcumin resulted in reduced soluble amyloid levels and plaque burden. these data raise the possibility that dietary supplementation with curcumin may provide a potential preventative treatment for ad by decreasing aβ levels and plaque load via inhibition of aβ oligomer formation and fibrillization, along with decreasing oxidative stress and inflammation. the interest in dietary dha supplementation has arisen from the approach to protect neurons from neuronal degradation and therefore prevent neurological diseases like ad. converging epidemiological data suggests that a low dietary intake of ω-3 polyunsaturated fatty acids is a candidate risk factor for ad (calon et al., 2005). in the ad brain, dha is known to be decreased (soderberg et al., 1991; prasad et al., 1998), while people who ingest higher levels of dha are less likely to develop ad (conquer et al., 2000; barberger-gateau et al., 2002; morris et al., 2003). a recent in vitro study by florent et al. demonstrated that dha provided cortical neurones with a higher level of resistance to the cytotoxic effects induced by soluble aβ oligomers (florent et al., 2006). lukiw et al. also demonstrated that dha decreased aβ40 and aβ42 secretion from aging human neuronal cells (lukiw et al., 2005). a study by calon et al. showed that a reduction of dietary ω-3 pufa in tg2576 transgenic mice resulted in a loss of post-synaptic proteins and behav- ioral deficits, while a dha-enriched diet prevented these effects (calon et al., 2004). other studies have shown that dha protects neurons from aβ accumulation and toxicity and ameliorates cognitive impairment in rodent models of ad (hashimoto et al., 2005; lim et al., 2005). a recent study by cole and frautschy showed that dha supplementation in tg2576 transgenic mice aged 17 months markedly reduced aβ accumulation, oxidative damage, and also improved cognitive function (cole and frautschy, 2006). thus, dietary supplementation with dha may also provide a potential preventative treatment for ad via prevention of cognitive deficits and reduction of aβ accumulation and oxidative stress. |
51 | lipoic acid as an anti-inflammatory and neuroprotective treatment karelson, e., bogdanovic, n., garlind, a., winblad, b., zilmer, k., kullisaar, t., vihalemm, t., kairane, c., zilmer, m. (2001) the cerebrocortical areas in normal brain aging and in alzheimer’s disease: noticeable differences in the lipid peroxidation level and in anti- oxidant defense. neurochem res, 26, 353–361. lander, h.m., tauras, j.m., ogiste, j.s., hori, o., moss, r.a., schmidt, a.m. (1997) activation of the receptor for advanced glycation end products triggers a p21(ras)- dependent mitogen-activated protein kinase pathway regulated by oxidant stress. j biol chem, 272, 17810–17814. levites, y., amit, t., mandel, s., youdim, m.b. (2003) neuroprotection and neurorescue against abeta toxicity and pkc-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol (-)-epigallocatechin-3-gallate. faseb j, 17, 952–954. lim, g.p., calon, f., morihara, t., yang, f., teter, b., ubeda, o., salem, n., jr., frautschy, s.a., cole, g.m. (2005) a diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged alzheimer mouse model. j neurosci, 25, 3032–3040. lim, g.p., chu, t., yang, f., beech, w., frautschy, s.a., cole, g.m. (2001) the curry spice curcumin reduces oxidative damage and amyloid pathology in an alzheimer transgenic mouse. j neurosci, 21, 8370–8377. liu, r.h. (2004) potential synergy of phytochemicals in cancer prevention: mechanism of action. j nutr, 134, 3479s–3485s. liu, j., killilea, d.w., ames, b.n. (2002) age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-l-carnitine and/or r-alpha -lipoic acid. proc natl acad sci usa, 99, 1876–1881. lovell, m.a., xie, c., xiong, s., markesbery, w.r. (2003) protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid. j alzheimer’s dis, 5, 229–239. lukiw, w.j., cui, j.g., marcheselli, v.l., bodker, m., botkjaer, a., gotlinger, k., serhan, c.n., bazan, n.g. (2005) a role for docosahexaenoic acid-derived neuroprotectin d1 in neural cell survival and alzheimer disease. j clin invest, 115, 2774–2783. maclean, c.h., issa, a.m., newberry, s.j., mojica, w.a., morton, s.c., garland, r.h., hilton, l.g., traina, s.b., shekelle, p.g. (2005) effects of omega-3 fatty acids on cogni- tive function with aging, dementia, and neurological diseases. evid rep technol assess (summ), 1–3. morris, m.c., evans, d.a., bienias, j.l., tangney, c.c., bennett, d.a., wilson, r.s., aggarwal, n., schneider, j. (2003) consumption of fish and n-3 fatty acids and risk of incident alzheimer disease. arch neurol, 60, 940–946. muller, u., krieglstein, j. (1995) prolonged pretreatment with alpha-lipoic acid protects cul- tured neurons against hypoxic, glutamate-, or iron-induced injury. j cereb blood flow metab, 15, 624–630. münch, g., gerlach, m., sian, j., wong, a., riederer, p. (1998) advanced glycation end prod- ucts in neurodegeneration: more than early markers of oxidative stress? ann neurol, 44, s85–s88. münch, g., shinto, l., maczurek, a. (2010) lipoic acid as a treatment for alzheimer’s disease. medicine today, 11, 62–64. ng, t.p., chiam, p.c., lee, t., chua, h.c., lim, l., kua, e.h. (2006) curry consumption and cognitive function in the elderly. am j epidemiol, 164, 898–906. nordberg, a., nyberg, p., adolfsson, r., winblad, b. (1987) cholinergic topography in alzheimer brains: a comparison with changes in the monoaminergic profile. j neural transm, 69, 19–32. nordberg, a., winblad, b. (1986) reduced number of [3h]nicotine and [3h]acetylcholine binding sites in the frontal cortex of alzheimer brains. neurosci lett, 72, 115–119. |
52 | natural medicines, nutraceuticals and neurocognition packer, l., witt, e.h., tritschler, h.j. (1995) alpha-lipoic acid as a biological antioxidant. free radic biol med, 19, 227–250. pocernich, c.b., butterfield, d.a. (2003) acrolein inhibits nadh-linked mitochondrial enzyme activity: implications for alzheimer’s disease. neurotox res, 5, 515–520. pocernich, c., la fontaine, m., butterfield, d. (2000) in-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain. neurochem int, 36, 185–191. prasad, m.r., lovell, m.a., yatin, m., dhillon, h., markesbery, w.r. (1998) regional mem- brane phospholipid alterations in alzheimer’s disease. neurochem res, 23, 81–88. quinn, j.f., bussiere, j.r., hammond, r.s., montine, t.j., henson, e., jones, r.e., stackman, r.w., jr. (2007) chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged tg2576 mice. neurobiol aging, 28, 213–225. retz, w., gsell, w., münch, g., rosler, m., riederer, p. (1998) free radicals in alzheimer’s disease. j neural transm suppl, 54, 221–236. rezai-zadeh, k., shytle, d., sun, n., mori, t., hou, h., jeanniton, d., ehrhart, j., townsend, k., zeng, j., morgan, d., hardy, j., town, t., tan, j. (2005) green tea epigallocatechin-3- gallate (egcg) modulates amyloid precursor protein cleavage and reduces cerebral amy- loidosis in alzheimer transgenic mice. j neurosci, 25, 8807–8814. seaton, t.a., jenner, p., marsden, c.d. (1996) the isomers of thioctic acid alter c-deoxyglucose incorporation in rat basal ganglia. biochem pharmacol, 51, 983–986. shanmugam, k., holmquist, l., steele, m., stuchbury, g., berbaum, k., schulz, o., garcía, o.b., castillo, j., burnell, j., rivas, v.g., dobson, g., münch, g. (2008) plant- derived polyphenols attenuate lipopolysaccharide-induced nitric oxide and tumour necrosis factor production in murine microglia and macrophages. mol nutr food res, 52, 427–438. soderberg, m., edlund, c., kristensson, k., dallner, g. (1991) fatty acid composition of brain phospholipids in aging and in alzheimer’s disease. lipids, 26, 421–425. solfrizzi, v., panza, f., capurso, a. (2003) the role of diet in cognitive decline. j neural transm, 110, 95–110. steele, m., stuchbury, g., münch, g. (2007) the molecular basis of the prevention of alzheimer’s disease through healthy nutrition. exp gerontol, 42, 28–36. stuchbury, g., münch, g. (2005) alzheimer’s associated inflammation, potential drug targets and future therapies. j neural transm, 112, 429–453. suh, j.h., moreau, r., heath, s.h., hagen, t.m. (2005) dietary supplementation with (r)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of anti- oxidants in the rat cerebral cortex. redox rep, 10, 52–60. suh, j.h., shenvi, s.v., dixon, b.m., liu, h., jaiswal, a.k., liu, r.m., hagen, t.m. (2004a) decline in transcriptional activity of nrf2 causes age-related loss of glutathione synthe- sis, which is reversible with lipoic acid. proc natl acad sci usa, 101, 3381–3386. suh, j.h., zhu, b.z., deszoeke, e., frei, b., hagen, t.m. (2004b) dihydrolipoic acid lowers the redox activity of transition metal ions but does not remove them from the active site of enzymes. redox rep, 9, 57–61. tully, a.m., roche, h.m., doyle, r., fallon, c., bruce, i., lawlor, b., coakley, d., gibney, m.j. (2003) low serum cholesteryl ester-docosahexaenoic acid levels in alzheimer’s disease: a case-control study. br j nutr, 89, 483–489. watson, g.s., craft, s. (2003) the role of insulin resistance in the pathogenesis of alzheimer’s disease: implications for treatment. cns drugs, 17, 27–45. wong, a., dukic-stefanovic, s., gasic-milenkovic, j., schinzel, r., wiesinger, h., riederer, p., münch, g. (2001a) anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia. eur j neurosci, 14, 1961–1967. |
53 | lipoic acid as an anti-inflammatory and neuroprotective treatment wong, a., lüth, h.j., deuther-conrad, w., dukic-stefanovic, s., gasic-milenkovic, j., arendt, t., münch, g. (2001b) advanced glycation endproducts co-localize with induc- ible nitric oxide synthase in alzheimer’s disease. brain res, 920, 32–40. yang, f., lim, g.p., begum, a.n., ubeda, o.j., simmons, m.r., ambegaokar, s.s., chen, p.p., kayed, r., glabe, c.g., frautschy, s.a., cole, g.m. (2005) curcumin inhibits forma- tion of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. j biol chem, 280, 5892–5901. zhang, l., xing, g.q., barker, j.l., chang, y., maric, d., ma, w., li, b.s., rubinow, d.r. (2001) alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the akt signalling pathway. neurosci lett, 312, 125–128. zhao, b.l., li, x.j., he, r.g., cheng, s.j., xin, w.j. (1989) scavenging effect of extracts of green tea and natural antioxidants on active oxygen radicals. cell biophys, 14, 175–185. |
54 | metabolic agents and cognitive function glucose and oxygen the principal source of energy for brain function is derived from the oxidative breakdown of glucose. the human brain is an extremely metabolically active organ accounting for approximately 30% of the total basal energy expenditure. the brain remains metabolically active at all times, including sleep, and is thus entirely depen- dent on continuous and uninterrupted supply of energy in the form of the substrates glucose and oxygen. compared to other organs in the body, the brain is particularly vulnerable to small and transient changes in its energy supply. interrupted delivery leads within seconds to unconsciousness and within minutes may cause irrepara- ble brain damage. thus, the concentration of glucose in the blood plasma is tightly regulated to stay within the normal range of 60–90 mg/100 ml for humans. when blood glucose drops below 40 mg/100 ml (hypoglycemic condition) in humans, it can cause discomfort, confusion, coma, convulsions, or even death (lehninger et al. 2005). beyond infancy, and under normal conditions, the brain’s energy require- ments are met almost exclusively by the oxidative breakdown of glucose. during times of hypoglycemia other tissues will cease to utilize glucose all together in order to increase glucose availability to the brain (thomson 1967). compared with other organs the brain possesses paradoxically limited stores of glycogen, which without replenishment are exhausted in up to 10 min. there is, however, no storage capacity for oxygen; thus, disruption leads to instantaneous effects. associated measurements of oxygen and glucose levels in blood sampled upon entering and leaving the brain in humans show that almost all the oxygen utilized by the brain can be accounted for by the oxidative metabolism of glucose (mcilwain 1959). since the brain is clearly susceptible to small changes in energy supply, metabolic activity is limited by glu- cose and oxygen resources. a few early studies demonstrated the effects of glucose on cognition around the 1950s. for example, administration of 10 g of glucose to school children every 45 min throughout a morning demonstrated improved mathematical ability and generally improved concentration (hafermann 1955). however, a more widespread interest in glucose did not occur until the 1980s when the glucose effect was reevalu- ated by psychopharmacologists examining possible mechanisms of action for neuro- endocrine facilitation of memory. since then there have been increasing reports that cognitive functioning is influenced by the increased availability of glucose provi- sion. many reports have illustrated the robust association between changes in blood glucose levels and cognition in animals (gold 1986; wenk 1989; white 1991), the elderly (gonder-frederick et al. 1987; craft et al. 1992, 1994), and the young (benton and sargent 1992; benton and owens 1993; sünram-lea et al. 2001, 2002a,b, 2004; riby et al. 2008; scholey et al. 2009). thus, the cognition-enhancing action of glu- cose is well established. in terms of dosing the most optimal glucose dose for cogni- tive enhancement generally appears to follow the classic yerkes–dodson inverted-u dose–response profile (sunram-lea et al. 2011). for young adults 25 g seems to most reliably facilitate cognitive performance; however, there is some contention regarding whether the dose–response profile may be dependent upon the cognitive domain being assessed. in rats bimodal response variability was observed when dif- ferent tasks were used which represented the action of glucose on two different brain |
55 | natural medicines, nutraceuticals and neurocognition substrates: the caudate nucleus and the hippocampus (packard and white 1990). in humans the inverted-u dose–response profile has been specifically observed for tasks of verbal declarative memory, where other tasks (specifically spatial and numeric working memory) demonstrated slightly different response profiles (cubic and quartic respectively) (sunram-lea et al. 2011). the clearest enhancement effects of increased glucose supply have been observed for declarative memory tasks in the form of word and paragraph recall; for a review see hoyland et al. (2008). these findings have led to the notion that glucose facilitation may be particularly pro- nounced in tasks which pertain to the hippocampal formation (sünram-lea et al. 2001). furthermore several studies have shown that an important mediating factor for cognitive enhancement by increased energy resources is level of task demands. that is, tasks which are more demanding appear to be more sensitive to the effect of glucose (kennedy and scholey 2000; scholey et al. 2001; sünram-lea et al. 2002a). it has also been demonstrated that tasks which are more demanding lead to a signifi- cantly accelerated reduction in blood glucose levels compared with a semantically matched task (scholey et al. 2001). however recent research has shown that at high dosages (60 g) implicit memory which is not regarded as either demanding nor hip- pocampally mediated may also be enhanced by glucose (owen et al. 2010), adding further support to the notion that different domains of memory may follow different glucose dose–response profiles. it is widely acknowledged that oxygen restriction and ischemic deprivation exert marked effects on cognitive function (volpe and hirst 1983). furthermore restric- tion of oxygen supply due to altitude results in cognitive impairment on a number of cognitive parameters with these effects being instantaneously reversed by the administration of oxygen (crowley et al. 1992). evidence suggests that even small fluctuations in cerebral oxygen delivery within normal physiological limits may impact on cognitive performance (walker and sandman 1979). while cognitive defi- cits from oxygen restriction due to altitude (crowley et al. 1992), carbon monoxide poisoning (weaver et al. 2002), and isovolemic anemia (weiskopf et al. 2002) can all be reversed by oxygen administration, impairment effects may be permanent if treatment is not administered in time. similarly cognitive degeneration due to age is not reversed by oxygen treatment when administered either normobaric or hypo- baric oxygen treatment (raskin et al. 1978). there is very limited research of oxygen administration on cognition in normal healthy individuals. early research examining the effects of hyperbaric oxygen supplementation demonstrated improved cognitive function (short-term memory and visual organization) in elderly outpatients com- pared to baseline performance. however this study failed to compare with a control group (edwards and hart 1974). in normal healthy humans research has demonstrated that oxygen administra- tion can improve cognitive functioning compared to air-breathing control condi- tions. research has shown that oxygen administration leads to improved long-term memory and reaction times compared to a control group of normal air-breathing (moss and scholey 1996; moss et al. 1998; scholey et al. 1998). furthermore, similar to glucose facilitation, oxygen administration appears to facilitate cognition most effectively for tasks with a higher cognitive load (moss et al. 1998; scholey et al. 1998). in addition to this finding a further study also examined heart rate during |
56 | metabolic agents and cognitive function cognitive testing with oxygen versus air-breathing controls. compared to baseline, heart rate was significantly elevated during cognitive testing tasks in both the air and oxygen groups. in the oxygen group, significant correlations were found between changes in oxygen saturation and cognitive performance. in the air group, greater changes in heart rate were associated with improved cognitive performance (scholey et al. 1999). these findings suggest that during times of cognitive demand avail- ability of metabolic resources impact on cognitive functioning. a more recent study has further demonstrated the importance of metabolic resources during cognitive demand by manipulating level of cognitive demand during oxygen administration. in this study oxygen administration of 40% versus 21% was examined during comple- tion of an addition task with three levels of difficulty. it was observed that 40% oxygen improved accuracy scores across the task compared to the 21% oxygen dose, with the difference in accuracy rate increasing between the two dosages as the task difficulty level increased (chung et al. 2008). while cognitive demand is clearly a moderating factor for cognitive enhancement by oxygen, enhancement has been observed on several cognitive domains; for example, oxygen supplementation has been shown to improve everyday memory tasks such as memory for shopping lists and putting names to faces when participants received 100% oxygen compared with air-breathing controls (winder and borrill 1998). the dose–response for oxygen administration on performance appears to follow the yerkes–dodson inverted-u shape in a similar fashion to glucose facilitation with shorter doses of 30 s to 3 min appearing to be most beneficial while continuous oxygen breathing for longer than 10 min leading to decline in performance (moss et al. 1998). the window for cogni- tive improvement through oxygen administration therefore appears to be quite brief, with research demonstrating that administration of oxygen increases blood oxygen levels for only 4–5 min (moss et al. 1998). pyruvate neuronal cell death resulting from hypoglycemia and hypoxia is the result of a series of events triggered by reduced energy availability, and the normalization of blood glucose and oxygen levels does not necessarily block or reverse this cell death process once it has begun. during times of low availability of glucose and oxygen the brain utilizes other, less efficient energy sources that can be produced aerobically. pyruvate is the end product of glycolysis, which is converted into acetyl coenzyme a that enters the krebs cycle when there is sufficient oxygen available. when the oxygen is insufficient, pyruvate is broken down anaerobically, creating lactate in humans and animals. lactate has recently been considered as a central neuroprotective agent (gladden 2004). the blood-brain barrier normally transports pyruvate at a rate much slower than glucose, but prior work suggests that significant pyruvate entry to the brain can be achieved by elevating plasma pyruvate concentrations (lee et al. 2001). during pathological insult or general aging, the main upstream event most responsible for neuronal cell death is excitotoxicity from glutamate receptor activity (wieloch 1985). recent research has shown that cells that would otherwise go on to die after the cascade of excitotoxic activity could be rescued by providing pyruvate (ying et al. 2002). |
57 | natural medicines, nutraceuticals and neurocognition however, there is remarkably little research evaluating the effects of pyruvate on cognitive function. one recent study assessed the effect of pyruvate administration in rats with hypoglycemia-induced brain injury. insulin was used to induce hypogly- cemia then hypoglycemia was terminated with either glucose alone or with glucose plus pyruvate. they found that in the four brain regions studied (ca1, subiculum, dentate gyrus of the hippocampus, and piriform cortex) the addition of pyruvate reduced neuron death by 70%–90%. neuron survival was also observed when pyru- vate delivery was delayed for up to 3 h. the improved neuron survival was accom- panied by a sustained improvement in cognitive function as assessed by the morris water maze (suh et al. 2005). furthermore recent animal research has demonstrated the potential usefulness of ethyl pyruvate as a stroke therapy. yu et al. (2005) found that ethyl pyruvate affords the strong protection of delayed cerebral ischemic injury with significant reduction in infarct volume accompanied by the suppression of the clinical manifestations associ- ated with cerebral ischemia, including motor impairment and neurological deficits. there are, as yet, no studies evaluating the effects of pyruvate administration on cognitive function in humans; however, pyruvate may be a good candidate for further research in those with energetic depletion and neurodegenerative diseases. impaired energy metabolism is an early, predominant feature in alzheimer’s disease and it is believed that impaired cerebral oxidative glucose metabolism is responsible, at least in part, for cognitive impairment in ad. research has demonstrated that in both animals and humans increased cerebrospinal pyruvate is a biomarker for ad (parnetti et al. 1995; pugliese et al. 2005). since pyruvate appears to be quite safe, aside from mild side effects, such as occasional stomach upset and diarrhea, pyruvate therapy might represent an excellent candidate for therapy in disease states accompanied by energy depletion. creatine creatine (cr) is a naturally occurring substance found in vertebrates and is essential for maintaining energy homeostasis. cr participates in metabolic reactions within cells and eventually is catabolized in the muscles creating creatinine, which is then excreted by the kidney in urine. in the average-sized adult (70 kg) cr store is approx- imately 120 g, with the daily turnover of cr to creatinine being estimated to be about 1.6% of the body’s total cr (balsom et al. 1995). the daily requirement of cr either through diet or endogenous synthesis is suggested to be approximately 2 g/day (walker 1979). since cr is concentrated in muscle tissue dietary sources of cr are fish and red meat, with a much lower concentration found in some plants (balsom et al. 1995). unsurprisingly cr levels of vegetarian or vegan individuals are much lower than omnivores. in a typical omnivorous diet between 0.25 and 1 g of cr per day is obtained. it appears that cr derived from the diet, after passing through the intestinal lumen, enters the bloodstream intact (conway and clark 1996). cr is stored in the high-energy form of phosphocreatine (pcr). pcr acts as a high-energy reserve in a coupled reaction in which energy derived from donating a phosphate group is used to regenerate the compound atp. pcr plays a particularly |
58 | natural medicines, nutraceuticals and neurocognition attributes of cr in supplemented animals. these data provide a strong rationale for examination of cr supplementation on the brain and cognition in the human model. despite the obvious impact cr has on brain development and metabolic actions in the brain, there are relatively few studies assessing the effects of cr on cogni- tive performance in humans. one study assessed the effect of 20 g cr supplemen- tation over 7 days in sleep-deprived individuals, following 24 h sleep deprivation. individuals who received cr supplementation demonstrated significantly reduced decrement in performance on a number of mood, cognitive, and physical perfor- mance parameters including random movement generation, choice reaction time, balance, and mood state (mcmorris et al. 2006). in a further study following 36 h sleep deprivation, cr-supplemented individuals also demonstrated improved perfor- mance on a random number generation task (mcmorris et al. 2007b). these studies appear to demonstrate benefits of cr supplementation in young individuals who are temporarily cognitively impaired through sleep deprivation. however, these studies were considerably underpowered having no higher than 10 participants per group. cr supplementation has also been demonstrated to improve cognition in individuals who are not cognitively impaired. one study assessed the effects of 8 g cr per day for 5 days in healthy individuals and demonstrated reduced mental fatigue when subjects repeatedly perform a simple mathematical calculation. after cr supplementation, task-evoked increase of cerebral oxygenated hemoglobin in the brains of subjects and reduced cerebral oxygenated hemoglobin (measured by near-infrared spectros- copy) was significantly reduced, which is compatible with increased oxygen utiliza- tion in the brain (watanabe et al. 2002). again, however, this study appeared to be rather underpowered with only 12 participants per group. nonetheless, it appears that cr supplementation may impact on cognitive function even over a relatively short period of time as these studies assessed the effects of acute supplementation over periods of 5–7 days. a more recent study assessed the impact of a new form of creatine, creatine ethyl ester, over a 2 week period (5 g/day dose compared to dextrose control group) in healthy 18–24 year old participants. the overall findings demonstrated consistent improvements for reaction time across a range of measures as well as improved accuracy on some and also improved iq scores. the most mod- est improvements appeared to be on tasks that were less demanding, indicating that creatine supplementation may be particularly useful when performing particularly demanding or complex cognitive tasks (ling et al. 2009). in chronic administration conditions, one study examining cr supplementation in young healthy adults failed to observe any effect of cr on cognitive performance (rawson et al. 2008). in this study 0.03 g/kg was administered daily for 6 weeks and a battery of neurocognitive tests was administered to asses cognitive processing and psychomotor performance including simple reaction time, code substitution, code substitution delayed, logical reasoning symbolic, mathematical processing, running memory, and sternberg memory recall. no effect of cr was observed on any of these outcome measures. however, research examining young adults who only produce cr endogenously (vegetarian sample), cr supplementation was shown to improve cognitive perfor- mance following chronic administration (6 week period) (rae et al. 2003). in this work, 5 g cr supplementation (cr monohydrate) was administered per day for 6 weeks |
59 | metabolic agents and cognitive function to 45 young vegetarian adults in a counterbalanced cross-over design. they observed that cr supplementation had a significant positive effect on both working memory (backward digit span) and intelligence (raven’s advanced progressive matrices). the pattern emerging from the present literature examining cr and cognitive func- tion appears to demonstrate that cognition is ameliorated specifically during times of metabolic impairment or depletion, either through low creatine availability (vegan and vegetarian samples) or by inducement (sleep deprivation or high cognitive demand). furthermore, since there is some evidence that creatine supplementation improves cog- nitive function in young, non-vegetarian, healthy individuals over shorter periods of administration (5 days to 2 weeks) but not longer periods (6 weeks) it may be the case that creatine supplementation might merely have been redressing nutritional imbalances. since elderly populations are generally metabolically impaired and often nutri- tionally deficient, it seems likely that elderly and degenerative populations would most benefit from creatine interventions over time. to our knowledge only one study has assessed the impact of cr supplementation in an elderly human population. mcmorris et al. (2007a) administered 20 g of cr per day for 7 days which resulted in improved performance of random number generation, forward and backward number and spatial recall, and long-term memory tasks but no effect on backward recall performance (mcmorris et al. 2007b). in terms of neurodegeneration, there has been no research examining the effects of creatine supplementation in dementia sufferers; however, there appears to be some differences in creatine levels in those with genetic risk of developing dementia (apolipoprotein ε4 carriers). laakso et al. (2003) demonstrated that compared with the noncarriers, the levels of creatine were significantly lower in the ε4 carriers. this finding may suggest increased metabolic demands in the brain of the ε4 carriers. they also observed that the levels of creatine also correlated significantly with age and performance on the mini-mental state examination test in the ε4 carriers, but not in the noncarriers (laakso et al. 2003). creatine supplementation in this sample seems like a logical next step for creatine and cognitive function research. despite the obvious potential benefits of cr supplementation, there is considerable lack of research examining the cognitively enhancing capabilities of cr and a number of questions remain to be answered. firstly there has been no research examining whether an acute administration of one single dose of cr can affect cognitive per- formance. secondly the only study to examine the effects of cr on cognition in the elderly was only over a period of 7 days. further to this there has been no examination of the usefulness of creatine in dementia research where there appears to be some evidence that creatine may be of particular therapeutic value. since the evidence seems to suggest that cr acts to buffer intracellular energy levels and potentially impede the progression of neurodegenerative processes a more systematic evaluation of cr mapping cognitive performance over a more substantial timeframe is required. carnitine/acetyl-l-carnitine in animals and humans, carnitine is biosynthesized primarily in the liver and kid- neys from the amino acids lysine or methionine (steiber et al. 2004) with vitamin c (ascorbic acid) being essential to the synthesis of carnitine. in food, the highest |
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