Natural Substances as Treatments for Age-Related Cognitive Declines

Cognitive function has long been known to decline with normal ageing, and recent findings indicate that this decline starts in early adulthood. While these declines are recognised, there is currently no regulatory acceptance to encourage the pharmaceutical industry to develop medicines to treat these normal age-related deterioration; and the industry is therefore currently focused on Alzheimer’s and other dementias, as well as prodromes for Alzheimer’s disease including Mild Cognitive Impairment. Recent surveys have shown that students, various professional groups, and the military are using ‘smart drugs’ like modafinil off-label to promote cognitive function, and such use is producing much controversy, due in part to the possible safety risks associated with such use.

However, a growing body of data is accumulating showing that naturally occurring substances can enhance cognitive function, even in young volunteers. This provides an alternative strategy for individuals who wish to optimise their mental performance and to attempt to correct age-related declines, i.e. by consuming naturally occurring substances which are more widely available. Accepting that naturally occurring substances can have the same range of health risks as prescription medicines, this paper considers research findings that could provide a rationale for self-medication of cognitive function with natural substances.

Bostrom and Sandberg (2009) define cognition enhancement as “the amplification or extension of core capacities of the mind through improvement or augmentation of internal or external information processing systems.” Aspects of cognitive function that are targets for enhancement include attention, vigilance, information processing, memory, planning, reasoning, decision making, and motor control. Bostrom and Sandberg argue that an intervention aimed at correcting a specific pathology or defect of a cognitive subsystem may be characterized as therapeutic, while enhance-ment is an intervention that improves a subsystem in some way other than repairing something that is broken or remedying a specific dysfunction. This distinction is interesting, and accurately characterizes the various compounds which are being developed and studied in this rapidly growing field.

Substances to enhance cognitive function are currently receiving a large amount of public interest and ethical debate (Cakic, 2009), due to the recognition of their widespread use by students, the military, and many professional groups (Sahakian and Morein-Zamir, 2007). In 2008, the journal Nature reported the results of an online poll, in which 20% of the 1400 respondents admitted that they had used “neuro-enhancers” to stimulate their focus, concentration, or memory (Maher, 2008). Although 96% of respondents felt that individuals with neuropsychiatric disorders who have severe memory and concentration problems should receive such substances, 80% of respondents felt that anyone who wanted such substances should be allowed access, and 69% said they would take one provided the side-effects were low. The high level of interest can be illustrated by articles in The Times Online (Bannerman, 2010) entitled “Bring smart drugs out of the closet, experts urge Government,” and in Time Magazine entitled “Popping Smart Pills: The Case for Cognitive Enhancement” (Szalavitz, 2009).

Cognitive function concerns mental abilities which enable us to conduct the activities of daily living. Some aspects of cognitive function are relatively stable and unaffected by, for example, aging, fatigue, drugs, or trauma; while other aspects such as attention and memory are variable by nature and highly susceptible to change. Tests of cognitive function assess how well various cognitive skills are operating in an individual at any particular time. Such evaluations require individuals to perform tasks which involve one or more cognitive domains. Thus if a researcher wished to assess memory, the test would involve the memorization of information and the outcome measure would reflect how well such information could be retrieved. Equally, to assess the ability to sustain attention, the test could involve monitoring a source of information in order to detect predefined target stimuli over a period of time, and the outcome measures would reflect the speed and accuracy of the detections. It is important to note that the only way to measure cognitive function directly is by assessing the quality of performance on cognitive tests or behavioral tasks. It is of interest to assess how the individual feels about his or her levels of cognitive function, but this is sim-ply supportive evidence for the objective assessment of task performance. Similarly, various measures of brain activity (for example, electroencephalography and fMRI scanning) do not measure the quality of cognitive function directly, but rather provide us with independent but nonetheless hugely valuable information about the activation of certain brain areas as well as the interconnecting pathways between various areas which are crucial for successful completion of various cognitive operations.

It is important that the researcher in this field identifies the appropriate domain of cognitive function to investigate. While “cognition enhancement” is an acceptable generic term, as is “health promoting,” both science and regulators require more specific targets, which respect the independence of different domains when considering specific claims. For example, why in medicine would a drug which helped pulmonary function be expected to help the liver? This illustrates the limitation of global scores of cognition for nutritional claims, and should guide researchers to seek assessments of specific target domains of function. There are a number of core cognitive domains which can be evaluated, including attention, information processing, reason-ing, memory, motor control, problem solving, and executive function. Taking memory as an example, there are four major types: episodic or declarative memory, working memory, semantic memory, and procedural memory (see Budson and Price, 2005). As Budson and Price illustrate, relatively few conditions are associated with impairments to semantic memory and procedural memory, while working and episodic memory are impaired in a wide variety of neurological, psychiatric, surgical, and medical conditions. This creates a rationale for directing testing toward working and episodic memory as a more fruitful potential area to evaluate in novel conditions, and most test systems recognize this approach. Further, tests specific to particular domains are, when available, ideal, as this helps to facilitate the substantiation of any claims made on the basis of the research findings. The most specific tests are attentional tests, as well-designed tests of attention do not require aspects of memory or reasoning for task performance, and thus changes in performance can be relatively clearly attributable to effects on attentional processes. As attention is important for the performance of any task, when seeking to evaluate other domains, it is useful to also assess attention additionally in order that the relative contribution to any effects of changes to attention can be established. Most well-established test batteries include assessments of atten-tion, working and episodic memory, motor control, and aspects of executive function.

The automation of cognitive tests brings numerous advantages (e.g., Wesnes et al., 1999); the most relevant to the area of cognition enhancement is improving the signal-to-noise ratio. Noise, i.e., unwanted variability, is decreased by the standardization such testing can bring to test administration and the reduction of errors in scoring. However, the signal can also be increased due to the extra precision in assessment which millisecond resolution of response times can bring. Furthermore, aspects of cognitive function can be assessed, which cannot be measured using traditional pencil and paper measures. Major tests of attention such as simple and choice reaction time have always been automated, as have intensive vigilance tests like the continuous performance test and digit vigilance tasks. Further, computerized tests of verbal and object recognition permit, besides the assessment of the accuracy of 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 further important benefit of assessing speed is that it permits “speed-accuracy trade-offs” to be identified, which helps to avoid misinterpretations of study findings.

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).

Improvements must be identified by well recognized and extensively vali-dated tests of cognitive function.Improvements should be to one or more major domains of cognitive function.Improvements must be seen on core measures of task performance, and any suggestions of speed-accuracy trade-offs should be interpreted with caution.Improvements in one cognitive domain should not occur at the cost to another.Improvements should not be followed by rebound declines.Improvements should be of magnitudes which are behaviorally and clinically relevant.Improvements should not be subject to tachyphylaxis over the period for which the treatment is intended to be used.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 variety of aspects of cognitive functioning are poorer in the elderly. One consistent criticism of this approach is that the elderly group grew up in a different era, which may have limited their subsequent abilities (for example, due to socioeconomic fac-tors such as more limited educational abilities and poorer nutrition), and thus the differences may not simply have been due to aging. A research group based at the University of Virginia, the United States, led by Timothy Salthouse, has comprehensively investigated this area over the past few decades. The outcomes of this research program have been recently summarized (Salthouse, 2010). The approach of Salthouse and colleagues has been to assess thousands of healthy individuals across the age range on a variety of traditional neuropsychological tests and to evaluate the pattern of change by decade from early adulthood until the 1980s. The consistent finding has been for linear declines to be present in a range of measures of attention, information processing, reasoning, and various aspects of memory from the twenties onward. Using a variety of analytic techniques, the groups have established that despite com-mon assumptions to the contrary, age-related declines in measures of cognitive functioning are relatively large, begin in early adulthood, are evident in several different types of cognitive abilities, and are not always accompanied by increases in between-person variability. This pattern has also been identified over the same age range using computerized tests of cognitive function, showing linear declines in 5 year cohorts to the speed and accuracy of various aspects of attention, working and episodic memory (Wesnes and Ward, 2000; Wesnes, 2003, 2006).

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, cognitive 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 intellectual 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 subsequently 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 attention, 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 considered only after it has been determined that the cognitive impairment is not attributable to a specific mental disorder or neurological complaint”.

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

Natural Substances as Treatments for Age-Related Cognitive Declines

condition is to be 1.5 standard deviations poorer than age-matched controls on a recognized test of memory, which limits the condition to less than 10% of the population, which thus has no relevance for the majority of the population who are experiencing age-related cognitive decline. Further, despite some very large clinical trials of potential treatments for MCI, only occasional findings of enhancements have been identified in the condition (e.g., Newhouse et al., 2012). Part of the problem was that the endpoint of many trials was the rate of conversion to Alzheimer’s disease, which required long-term trials with large samples of patients, and the fact that in many trials the expected rate of conversion did not occur in the placebo-treated groups.

Amphetamine was the first synthetic compound shown to improve human cognitive function (e.g., Mackworth, 1965), and both caffeine and nicotine are widely recognized to improve aspects of cognitive function such as attention, even in non-habitual users (e.g., Wesnes and Warburton, 1984; Haskell et al., 2005). There is a commonly held opinion that normal individuals, especially the young, are operating at optimum levels and cannot be enhanced. However, there exist hundreds of studies that demonstrate acute improvements to attention and memory in healthy student populations with a wide variety of substances such as oxygen (Moss et al., 1998), chewing gum (Wilkinson et al., 2000), nicotine (Wesnes and Warburton, 1984), caffeine (Haskell et al., 2005), gingko biloba (Kennedy et al., 2000), amphetamine, and methamphetamine (Silber et al., 2006).

The reticence of regulatory bodies to accept age-related cognitive decline as a suitable condition for treatment is obviously at odds with current general medical practice which seeks to treat a huge variety of other age-related conditions, ranging from failing hearing and eyesight to hip replacement. In the absence of regulatory acceptance or any consistent pressure from advocate groups, individuals the world over are left alone to seek to attempt to preserve their cognitive abilities as they age through a variety of techniques including physical and mental exercise (e.g., brain training), as well as by taking “smart drugs.”

An alternative approach available to individuals who wish to minimize age-related declines in mental efficiency is to seek various natural and nutritional sub-stances which can be obtained “over the counter.” Certainly, there has been a large research effort over recent decades to evaluate the effects of natural therapies upon cognitive functioning. While many naturally occurring plant extracts are commonly misconstrued to be “safe,” the use in Eastern cultures over millennia of substances such as ginkgo biloba and ginseng has identified the general absence of side effects of such products. Ginkgo biloba, e.g., has been the subject of enduring worldwide research interest for the past four decades, and a large and generally consistent body of research identifying positive effects on cognitive function has been identified by various research groups in healthy young and elderly volunteers (e.g., D’Angelo et al., 1986; Brautigam et al., 1998; Kennedy et al., 2000) and mildly cognitively impaired elderly patients (e.g., Wesnes et al., 1987; Rai et al., 1991; Kleijnen and Knipschild, 1992). While large well-controlled trials have shown the ability of ginkgo to treat the cognitive deficits in patients with Alzheimer’s disease and other 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 standardized 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 improvements 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 subsequent analysis of these data showed that the magnitude of the improvement was sufficient 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 counter 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), guanfacine (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

are clearly essential to allow replication in different laboratories. Safety is of crucial concern; only substances which have an established safety profile should be evaluated, and safety should be carefully monitored in any clinical trial in this field. One large well-conducted study has just been accepted for publication, which satisfies these various requirements. The trial evaluated the effects of docosahexaenoic acid (DHA) on cognitive function in 485 elderly people who fulfilled the DSM-IV criteria described earlier for AACD (Yurko-Mauroa et al., 2010). Six months of supplementation was found to produce statistically reliable improvements to memory. Though the effect size of the improvement was small (0.19), as with the Wesnes et al. (2000) trial, the computerized cognitive assessment system used in the study had a normative data-base; and using this database the authors were able to identify that the effect reflected a 7 year reduction in normal aging (3.4 years when compared to placebo), which may well be attractive to the population studied (mean age 70 years). An important aspect of this study was the careful monitoring of safety, the adverse events not being different between the placebo and active treated groups. Besides being conducted to the rigorous standards required in this field and carefully monitoring safety, an important aspect of the study for future research was the presentation of effect sizes as well as an assessment of the potential “cognitive age-reducing” effect of treatment.