With increasing life expectancies and the maturation of the “baby boom” generation, adapting to the challenges posed by the aging population has been identified as one of the major issues facing contemporary Australian society (Australian Productivity Commission, 2005). For Australia, like many Western nations, human aging has significant societal, economic, health, and, importantly, personal costs. In purely economic terms, the costs of aging reflect decreased productivity as well as increased levels of reliance on public services to health and social support but this also has obvious ramifications for older citizens’ ability to lead fulfilling lives. Increasing age is associated with a cluster of illnesses involving oxidative stress, cardiovascular and respiratory disease, and, importantly, neurological conditions such as Parkinson’s disease and Alzheimer’s disease. The New Zealand Treasury has estimated that the cost to the public health system alone of individuals over 65 years of age is five times that of people under 65 (Bryant and Sonerson, 2006). The same report concludes that 33% of these increased costs could be offset by measures aimed at maintaining improved health, which of course also involves brain and cognitive processes.
A time-honored and much empirically supported method of promoting optimal health throughout the life span has been through the adoption and maintenance of an appropriate, healthy diet. Recent research suggests that this principle not only applies to protection from “physical ailments” such as cardiovascular problems, but may also extend to ameliorating the effects of cognitive decline associated with increased age. The maintenance of brain health underpinning intact cognition is a key factor to maintaining a positive, engaged, and productive lifestyle. In the light of this, the role of diet including supplementation with nutritional and even pharmacological interventions capable of ameliorating the neurocognitive changes that occur with age constitutes vital areas of research.
Individual age-related changes in cognition vary greatly. However, research in cognitive aspects of aging (typically in 60–90 year-olds) has identified consistent deficits in reasoning and decision making, spatial abilities, perceptual-motor and cognitive speed, and, most robustly, memory (e.g., Christensen and Kumar, 2003). Longitudinal studies of aged populations illuminate the time course of cognitive deterioration. Using 5–10 year retest intervals, significant decrements across most cognitive capacities become evident. A recent review of longitudinal aging studies concludes that crystallized intelligence (e.g., factual knowledge) remains intact until late aging whereas measures of speed, information processing, and aspects of memory (e.g., working memory) are more sensitive to decline from age 60 (Christensen and Kumar, 2003).
Neuroimaging studies reveal that increasing age is reliably associated with ventricu-lar enlargement, reduction in gross brain volume, reductions in frontal and temporo-parietal brain volume, higher levels of cortical atrophy, and increased white-matter hyperintensities (Looi and Sachdev, 2003). Ultimately, shrinkage of cortical volume reduces cognitive capacity (MacLullich et al., 2002), and age-related increases in neuropathological events such as ß-amyloid protein deposition and formation of neurofibrillary tangles represent significant risk factors. Neuropathological events such as ß-amyloid deposition are not exclusive to neurodegenerative disorders such as AD, in fact occurring in a large proportion of cognitively intact individuals. For example, in one study, the proportion of nonclinical subjects with ß-amyloid deposits ranged from 3% in a 36–40 age group to 75% in an 85+ age group (Braak and Braak, 1997). Alongside age-associated cortical degeneration (MacLullich et al., 2002), there exist numerous microscopic insults related to oxidative stress. Free radicals formed in the brain produce significant cellular damage and mediate processes that result in neural cell death on large scales (Packer, 1992). Between 95% and 98% of free radicals and reactive oxygen species (ROS), O2-, HO, and H2O2 are formed by mitochondria as by-products of cellular respiration. Studies of mitochondria isolated from the brain show that 2%–5% of total oxygen consumed yields ROS, and these highly reactive molecules make a significant contribution to the peroxidation of principal cell structures (e.g., membrane lipids) (Papa and Skulachev, 1997). Brain tissue is particularly susceptible due to its disproportionately high metabolic rate and levels of oxygen, the cytotoxic actions of glutamate, and its high concentrations of peroxidizable unsaturated fatty acids (Packer, 1992). Aging decreases the brain’s ability to combat the actions of free radicals. Aging is associated with increased levels of pro-oxidant mediators and decreases in antioxidants (Artur et al., 1992). The relationship between cognition and oxidative stress is evident in the extensive damage caused by free radicals in age-related neurological conditions (Coyle and Putfarcken, 1993; Smith et al., 1996) and animal models of age-related oxidative injury with central cognitive and behavioral impairments (Forster et al., 1996). Concurrent with the normal age-related cognitive changes are increases in the formation of brain ROS resulting in significant damage to DNA, proteins, and in particular membrane lipids (Smith et al., 1991). Although multiple factors precipitate oxidative stress throughout the body, the brain is particularly vulnerable, and its cumulative effects may account for the delayed onset and progressive nature of Alzheimer’s and Parkinson’s demen-tias as well as normal age-related mental deterioration (Coyle and Putfarcken, 1993).
The central role of oxidative stress in age-related cognitive decline and neurodegenerative diseases has driven numerous studies examining the potential benefits of antioxidants in altering, reversing, or forestalling neuronal and behavioral changes (e.g., Sano et al., 1997). Antioxidant supplementation results in improved cognition and behavior in aged animals and concurrent decreases in oxidative insult to neural structures (Socci et al., 1995). Human research in this area is largely limited to epidemiological studies. These have identified positive associations in aged individuals between biological levels of dietary antioxidants (vitamins E and C) and working memory measures including the Wechsler Memory test (Goodwin et al., 1983). Less reliable than biological measures, large-scale studies (3000+ participants) have also identified positive relationships between dietary intake of vitamins C and E and standardized memory measures (Masaki et al., 2000). While these nonclinical trials do not demonstrate causality, the consensus that memory is the main cognitive variable affected by antioxidant status is consistent with patterns of age-related cognitive decline and the in vivo neuroanatomy of lipid peroxidation (Sram et al., 1993). Three controlled studies of active antioxidant supplementation in aged individuals over periods of 1 year or longer reported improved performance on tests of short-term memory, verbal learning, and nonverbal memory (Sram et al., 1993; La Rue et al., 1997; Chandra, 2001). However, these studies did not incorporate indicators of oxidative stress, making it impossible to determine the role of antioxidants in the cognitive changes. Despite the great promise that antioxidant supplementation holds for understanding age-related mental deterioration, studies published in the area have been methodologically inadequate. In particular, human studies have thus far been severely limited by inappropriate cognitive measures, lack of biochemical indicators, uncontrolled subject populations, and unspecific antioxidant supplementation. One particular herbal medicine that may have some utility in treating pathological changes in the brain associated with age-related cognitive decline and that has been used in our laboratory is Bacopa monnieri (BM).
Bacopa monnieri (BM) is a botanical medicine from India that has been used for over 3000 years as a traditional ayurvedic treatment for asthma, insomnia, epilepsy, and as a “memory tonic” (Russo and Borrelli, 2005). BM has been used in traditional ayurvedic medicine for various indications including memory decline, inflammation, pain, pyrexia, epilepsy, and as a sedative (Russo and Borrelli, 2005). BM contains Bacoside A and bacoside B that are steroidal saponins believed to be essential for the clinical efficacy of the product. While BM has been reported to have many actions, its memory enhancing effects have attracted most attention and are supported by the psychopharmacology literature. Behavioral studies in animals have shown that BM improves motor learning, acquisition, retention, and delay extinction of newly acquired behavior (Singh and Dharwan, 1997). Although the exact mechanisms of action remain uncertain, evidence suggests that BM may modulate the cholinergic system and/or have antioxidant and metal-chelating effects (Agrawal, 1993; Bhattacharya et al., 1999). BM may also have antiinflammatory (Jain, 1994), anxiolytic and antidepressant actions (Bhattacharya and Ghosal, 1998), relaxant properties in blood vessels (Dar and Channa, 1999), and adaptogenic activity (Rai et al., 2003). Chronic administration of BM inhibits lipid peroxidation in the prefrontal cortex, striatum, and hippocampus via a similar mechanism to vitamin E (Bhattacharya et al., 2000). In an animal model of AD, there was a dose-related reversal by BM of cognitive deficits produced by the neurotoxins colchicine and ibotenic acid (Bhattacharya et al., 1999). In rodents, BM inhibited the damage induced by high concentrations of nitric oxide in astrocytes (Russo et al., 2003). Memory deficits following cholinergic blockade by scopolamine were reversed by BM treatment. In animal studies, BM reduced lipid peroxidation induced by FeSO4 and cumene hydroperoxide, indicating that, similarly to the chelating properties of EDTA, it acts at the initiation level by chelating Fe++ (Tripathi et al., 1996). More recently, in transgenic mice, BM supplementation reduced specific amyloid peptides by up to 60% while also improving memory performance (Holcomb, 2006). Thus, BM appears to have multiple modes of action in the brain all of which may be useful in ameliorating cognitive decline in the elderly. These include (1) direct procholinergic action, (2) antioxidant (flavonoid) capacity, (3) metal chelation, (4) antiinflammatory effects, (5) increased blood circulation, (6) adaptogenic activity, and (7) removal of ß-amyloid deposits.
Extracts of BM contain significant levels of saponic bacosides A, B, and C; and bacosapoinins D, E, and F, in addition to other chemical constituents including alka-loids, flavonoids, and phytosterols (Pengelly, 1997; Heinrich et al., 2004). The main chemical constituent of BM is bacoside A, which has been postulated to be responsible for the memory facilitating action of the plant (Russo and Borrelli, 2005). Bacoside A usually cooccurs with bacoside B that differs only in terms of its optical rotation. BM has been available in a standardized form since 1996 for clinical research (Singh and Dhawan, 1997).
Importantly, for both research and the community, the bacoside content does vary between manufacturers, as does the quality of the extract. Thus, clinical evidence from standardized high quality extracts cannot be extrapolated to other extracts. Higher level clinical studies typically use BM with bacoside content standardized to 50%–55%. Currently, most clinical evidence for a cognitive related effect from BM stems from one to two extracts including the extract CDRI08, which has been developed and studied extensively preclinically and in animals by the Indian Government (particularly the CDRI). Progressively, human trials on both CDRI08 and BM are now appearing with a particular emphasis on improving cognitive performance including memory.
A systematic review of the literature (Pase et al., in press) found eight human randomized controlled trials that met entry requirements (i.e., double-blinded, high quality studies). Of these studies, seven used chronic administration of BM while one was an acute study using a single 300 mg dose. No acute studies have to date shown a positive cognitive enhancement although there are current trials underway, and new data may shed some light on this possibility. However, based on the animal and in vitro studies on BM, it seems more likely that the mechanisms to improve cognition will exert influence chronically rather than acutely. Usually, acute cognitive enhancers or nootropic substances exert cognitive benefits via blood flow or direct neurotransmitter release. BM extracts are more likely to exert cognitive enhancement through inflammatory, antioxidant, or even removal of beta amyloid. The exact mechanism(s) are yet to be confirmed although large-scale mechanistic studies are now underway such as the Australian Research Council Longevity Intervention (Stough et al., 2012).
Chronic studies typically utilized a daily dose of 300 mg (standardized for baco-sides) for the duration of the study—nearly all studies use 3 months administration or similar (Stough et al., 2001; Roodenrys et al., 2002; Calabrese et al., 2008; Stough et al., 2008; Morgan and Stevens, 2010). In Roodenrys’ (2002) study, an increased dose of 400 mg/day was given to participants weighing over 90 kg. However, lower (250 mg/day) (Raghav et al., 2006) and higher doses of 450 mg/day (Barbhaiya et al., 2008) have been used chronically.
The human studies reviewed by Pase et al. (2012) provide evidence of highly promising results in areas of cognition, memory, and speed of processing tasks. Some studies used a healthy young adult population (Stough et al., 2001; Nathan et al., 2004; Stough et al., 2008), and others used “middle aged” (Roodenrys et al., 2002) or “elderly” populations (Calabrese et al., 2008). Progressively, aging populations will be targeted for BM supplementation, given current evidence for mode of action on the brain.
Regardless of the age of the population, BM consistently improved selected cognitive functions. For example, BM was shown to improve working memory (Stough et al., 2008), learning rate and memory consolidation, and other components of the Rey Auditory Verbal Learning Test (Stough et al., 2001; Calabrese et al., 2008; Morgan and Stevens, 2010) as well as improvements in memory measured by the Wechsler Memory Scale found in the Raghav et al. (2006) study. Furthermore, exec-utive functioning tasks, such as the stroop (Calabrese et al., 2008) and inspection time (Stough et al., 2001), have also shown to be improved by intervention with BM. The effect sizes on many domains were moderate to strong. BM on various out-come measures consistently improved cognition, memory, and speed of processing in older adults with an overall moderate effect on all measure of memory (mean d = 0.58). BM was also found to improve learning and memory (mean d = 0.61), working memory and executive function (mean d = 0.54), and visual processing and attention (mean d = 0.28).
BM has also been studied in the context of age-associated memory impairment (AAMI). Raghav et al. (2006) tested a sample of middle aged to elderly participants with AAMI. Participants receiving a standardized BM extract (250 mg/day) showed statistically significant improvement across subtests of the Wechsler Memory Scale from week 4 onward. Tasks of mental control, logical memory, and paired associated learning showed the greatest improvement. Clearly, these data are preliminary and need to be replicated. However, they support and reinforce the memory and cognitive enhancing effects of BM as well as an appropriate age-related target for intervention.
To date, only one study has been reported to assess the efficacy of BM in a sample of participants with dementia. A small 6 month pilot study has been carried out by Morgan and colleagues (see Morgan and Stevens, 2010) on participants diagnosed with mild–moderate dementia using BM (300 mg daily) as an adjunct intervention to their standard treatment. Participants (n = 5) were tested using the mini mental state examination (MMSE) and Alzheimer’s disease assessment scale (ADAS-cog; cognitive subscale) at baseline and 6 months. Both scales are valid measures of AD decline (Folstein et al., 1975; Kolibas et al., 2000). The BM intervention improved scores on both scales with 4/5 patients improving on the MMSE and 3/5 improving on the ADAS-cog (although there was a dissociation between the patient who improved on the two scales). These results are an indication that BM may have potential as an adjunct treatment for AD.
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