Grey matters: does Bacopa monnieri improve memory performance

Transcription

Southern Cross University
ePublications@SCU
Theses
2006
Grey matters: does Bacopa monnieri improve
memory performance in older persons
Annette Kay Morgan
Publication details
Morgan, AK 2006, 'Grey matters: does Bacopa monnieri improve memory performance in older persons', Masters thesis, Southern
Cross University, Lismore, NSW.
Copyright AK Morgan 2006
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Grey Matters: Does Bacopa monnieri
Improve Memory Performance in Older
Persons?
Annette Morgan ND DBM BNurs
A research thesis submitted in fulfilment of requirement of
the degree of Master of Science
Department of Nursing and Health Care Practices
July, 2006
Statement of Originality and Authenticity
I certify that the work presented in this thesis is, to the best of my knowledge and belief,
original, except as acknowledged in the text, and that the material has not been
submitted, either in whole or in part, for a degree at this or any other university.
I acknowledge that I have read and understood the University's rules, requirements,
procedures and policy relating to my higher degree research award and to my thesis.
I certify that I have complied with the rules, requirements, procedures and policy of
the University (as they may be from time to time).
Signed: .....................................................................
Date: .........................................................................
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Acknowledgements
Here, at the end of this thesis, the whole thing seems as though it was a straight forward
process. How quickly I have forgotten those long hours, weeks and months when the
end point seemed only a dim and distant point in time. I have many to thank for helping
me make it here- to the final stage of an arduous, yet also inspirational, journey.
Firstly, thanks to Val, Josh and Jesse for their ongoing love and support. Thanks to my
supervisor Dr John Stevens for guidance, encouragement, moral support and always
being available despite an excessive workload. Thanks to Ms Keelin Turner for expert
guidance with neuropsychological testing- and for sharing some of her inspirational
knowledge of the workings of the brain. Thanks to Dr Don McMurray for the many
hours of memory testing and the professionalism, warmth and humour he brought along
to the testing sessions. Thanks to Dr Joan O’Connor for always being willing to help
and advise.
Many thanks to Natural Remedies Pvt. Ltd. for supplying raw materials and funding.
Thanks to Herbs of Gold for supply of tablets and to Tabco Pty. Ltd. for the
manufacture and supply of placebo tablets. Thanks also to Michael Gepp and Miles
Wayne for facilitation of these negotiations. The generosity and support of these
companies made the research a feasible venture.
Lastly, I’d like to thank all of the people who responded to the call for research
participants- without them, especially, this research would not have been possible.
iii
Abstract
Background
This thesis investigated the efficacy and safety of Bacopa monnieri in improving
memory in healthy Australians over the age of 55-years. A review of the literature
showed that memory impairment and dementia are increasingly prevalent in the current
demographic climate of an ageing population. As well as the pathological cognitive loss
of neurodegenerative disease, many older persons are experiencing memory loss as part
of the physiological process of ageing.
Bacopa monnieri is a herbal medicine used since antiquity in the traditional Ayurvedic
medical system of India for its cognitive enhancing effects. A number of pre-clinical
and clinical studies support this traditional usage. Laboratory studies have demonstrated
antioxidant and cholinergic actions in the brain as well as improved memory and
cognitive performance in animal models.
Human trials of Bacopa have also demonstrated improved memory performance. Some
of these trials are limited by methodological flaws such as lack of blinding, small
sample sizes, or use of outcome measurements which are not well validated. However, a
small number of well designed human trials provide evidence for efficacy in cognitive
and memory performance improvement. The current study was employed to extend on
previous findings by assessing the efficacy and safety of Bacopa in the aged population
specifically, as it is in this population that memory impairment becomes apparent.
Aims
1. To assess the efficacy of Bacopa monnieri in improving memory in healthy
Australians over the age of 55-years.
2. To assess whether the use of Bacopa is associated with side-effects
Design
A 12-week, randomised, double-blind, placebo-controlled, parallel group clinical trial.
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Participants
Participants were self selected from the general population. They were aged 55-years or
over at the commencement of the trial. Participants were without dementia, depression
or other serious health conditions and did not use psychotropic medications.
Intervention
Participants were randomised to one of two treatment conditions, either a tableted
extract of Bacopa monnieri called Bacomind™ (300mg/day, standardised to contain at
least 40% bacosides), or an identical placebo.
Participants attended three clinical evaluations: the first an initial screening session, the
second a baseline evaluation of neuropsychological function and subjective memory
performance at the commencement of the trial and the third, an end-of-trial outcome
evaluation at 12-weeks, during which neuropsychological function and subjective
memory performance were again assessed along with side-effects and study
compliance.
Primary Outcome Measures
Rey Auditory Verbal Learning Test (AVLT), Rey-Osterrieth Complex Figure Test
(CFT), Memory Complaint Questionnaire (MAC-Q), and Trail Making Test (TMT)
Results
From 136 people who elected to participate, 103 people met study entry criteria and 98
of these commenced the trial. Of these, 81 participants completed the trial and provided
evaluable data for the end point analysis. Bacopa monnieri versus placebo significantly
improved verbal learning as well as delayed recall as measured by the AVLT (p<.05).
Though improvements were noted in the CFT, MAC-Q and TMT, there were no
significant differences between placebo and active groups found for these tests. The
Bacopa group reported a higher incidence of gastro-intestinal (GIT) side-effects than the
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placebo group, these predominantly being increased stool frequency, abdominal cramps
and nausea. No other significant adverse effects were found.
Conclusions
A clinical trial was carried out to assess the effects of 12-weeks administration of
Bacopa monnieri (300mg/day) on memory performance in people over the age of 55years. Primary outcome measures were well validated neuropsychological tests that
objectively measured verbal and visual memory and a memory complaint questionnaire
that measured subjective memory complaints.
The results demonstrated that Bacopa significantly improved memory acquisition and
retention in older Australians. This concurs with findings from previous human and
animal studies, as well as supports traditional Ayurvedic claims and uses. The beneficial
effects on memory observed may be due to previously demonstrated antioxidant and
cholinergic effects of the herb on the central nervous system.
The use of Bacopa was associated with GIT side-effects, particularly increased bowel
movements, nausea and abdominal cramping, findings infrequently reported previously.
Possible explanations for these side-effects include GIT irritation by the saponin
constituents of the herb, or cholinergic stimulation of autonomic and motor responses in
the GIT, or a combination of both of these factors. The side-effects observed in the
current study provide supportive evidence that Bacopa may increase cholinergic activity
in humans.
A worthwhile future extension of the current study would be to assess whether the
finding of Bacopa’s efficacy for improving memory performance is replicable in
populations with either mild cognitive impairment or early dementia.
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List of Abbreviations
AACD
age-associated cognitive decline
AAMI
age-associated memory impairment
ACh
acetylcholine
AChE
acetylcholinesterase
AD
Alzheimer’s disease
ADHD
attention deficit hyperactivity disorder
AIHW
Australian Institute of Health & Welfare
a-MCI
amnestic type of mild cognitive impairment
ANOVA
analysis of variance
ANS
autonomic nervous system
AVLT
Rey Auditory Verbal Learning Test
BM
Bacopa monnieri
CAM
complementary and alternative medicine
CFT
Rey-Osterrieth Complex Figure Test
ChAT
choline-acetyl transferase
CIND
cognitive impairment no dementia
CSIRO
Commonwealth Scientific and Industrial Research Organisation
CVD
cardiovascular disease
DB
double-blind
GIT
gastrointestinal tract
GLM
general linear model
HAM-D
Hamilton Depression Rating Scale
HIS
Hachinski Ischaemic Score
HREC
Human Research Ethics Committee
LTP
long term potentiation
MAC-Q
Memory Complaint Questionnaire
MCI
mild cognitive impairment
md-MCI
multiple domain mild cognitive impairment
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NFT
neurofibrillary tangles
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O
open
PC
placebo-controlled
PET
positron emission tomography
R
randomised
RDBPC
randomised, double-blind, placebo-controlled
SD
standard deviation
SPECT
single photon emission computed tomography
SPSS
statistical package for social sciences
TMT
Trail Making Test
TMT-A
Trail Making Test part A
TMT-B
Trail Making Test part B
WHO
World Health Organisation
WMH
white matter hyperintensities
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Table of Contents
Table of Contents ............................................................................................................ ix
List of Figures................................................................................................................. xii
List of Tables .................................................................................................................. xii
1. INTRODUCTION ........................................................................................................ 1
2. MEMORY AND AGEING .......................................................................................... 4
2.1 Introduction ............................................................................................................ 4
2.2 Cognition and memory - an overview .................................................................... 4
2.3 Memory and cognitive changes of normal ageing ................................................. 6
2.3.1 Speed of mental processing declines with ageing ........................................... 8
2.3.2 Fluid and crystallised cognitive abilities ......................................................... 9
2.3.3 Biological changes of brain ageing ................................................................. 9
2.4 Healthy brain ageing............................................................................................. 11
2.5 Conclusion ............................................................................................................ 11
3. THE PROBLEM OF DEMENTIA ............................................................................ 13
3.1 Introduction .......................................................................................................... 13
3.2 Demographic background: an ageing populace.................................................... 13
3.3 Dementia prevalence and cost .............................................................................. 14
3.4 Dementia pathologies ........................................................................................... 15
3.5 Therapeutic strategies for dementia...................................................................... 16
3.6 Pre-clinical dementia states .................................................................................. 18
3.7 Conclusion ............................................................................................................ 20
4: BACOPA MONNIERI............................................................................................... 22
4.1 Introduction .......................................................................................................... 22
4.2 History .................................................................................................................. 22
4.3 Constituents .......................................................................................................... 23
4.4 Pre-clinical and clinical studies of the cognitive effects of Bacopa ..................... 24
4.4.1 In vitro and animal studies ............................................................................ 24
4.4.2 Human trials .................................................................................................. 27
4.5 Conclusion ............................................................................................................ 32
5. RESEARCH DESIGN................................................................................................ 33
5.1 Introduction and overview.................................................................................... 33
ix
5.2 Location and timing.............................................................................................. 33
5.3 Ethical considerations........................................................................................... 33
5.4 Recruitment of participants .................................................................................. 34
5.4.1 Sample size.................................................................................................... 34
5.5 Procedures ............................................................................................................ 34
5.6 Selection criteria ................................................................................................... 35
5.6.1 Inclusion criteria ............................................................................................ 35
5.6.2 Exclusion criteria........................................................................................... 35
5.7 Study design ......................................................................................................... 36
5.7.1 Randomisation ............................................................................................... 36
5.8 Compliance........................................................................................................... 37
5.9 Materials ............................................................................................................... 37
5.9.1 Study drugs .................................................................................................... 37
5.10 Instruments ......................................................................................................... 38
5.10.1 Screening instruments.................................................................................. 38
5.10.2 Primary outcome measures.......................................................................... 39
5.11 Statistical analysis .............................................................................................. 41
6. RESULTS................................................................................................................... 43
6.1 Introduction .......................................................................................................... 43
6.2 Participants ........................................................................................................... 43
6.2.1 Exclusions...................................................................................................... 43
6.2.2 Randomisation ............................................................................................... 44
6.2.3 Effects of gender, marital status, age and education on baseline measures .. 46
6.2.4 Group distribution by age and gender categories. ......................................... 48
6.2.5 Compliance.................................................................................................... 50
6.2.6 Study withdrawals ......................................................................................... 50
6.2.7 Side-effects .................................................................................................... 52
6.3 Primary outcome measurements........................................................................... 54
7. DISCUSSION............................................................................................................. 60
7.1 Introduction .......................................................................................................... 60
7.2 Effects of age, gender and education on baseline measurements......................... 60
7.3 Primary outcome measures................................................................................... 61
7.3.1 The Rey Auditory Verbal Learning Test (AVLT) ........................................ 61
7.3.2 Rey-Osterrieth Complex Figure Test (CFT) and Trail Making Test (TMT) 64
x
7.3.3 The Memory Complaint Questionnaire (MAC-Q)........................................ 65
7.4 Possible mechanisms of action for observed effect of Bacopa ............................ 65
7.5 Side-effects ........................................................................................................... 67
7.6 Limitations of the current study............................................................................ 70
7.7 Recommendations arising from the study ............................................................ 72
8. CONCLUSION .......................................................................................................... 75
REFERENCES ............................................................................................................... 78
Appendix I: Participant instruction sheet and record booklet ........................................ 92
Appendix II: Human research ethics committee approval ............................................. 96
Appendix III: Participant consent form and information sheet ...................................... 99
Appendix IV: Clinical report form ............................................................................... 103
Appendix V: Neuropsychological test administration protocol ................................... 111
Appendix VI: Specification sheets for Bacopa and placebo tablets ............................. 112
Appendix VII: Rey Auditory Verbal Learning Test (AVLT) ...................................... 115
Appendix VIII: Rey Auditory Verbal Learning Test (AVLT) alternate form for endpoint
assessment .................................................................................................................... 117
Appendix IX: Rey-Osterrieth Complex Figure Test (CFT) ......................................... 119
Appendix X: Rey-Osterrieth Complex Figure Test (CFT) marking Sheet .................. 120
Appendix XI: Trail Making Test (TMT) parts A and B............................................... 122
Appendix XII: Memory Complaint Questionnaire (MAC-Q)...................................... 126
Appendix XIII: Results of repeated measures analysis for all variables...................... 127
xi
List of Figures
Figure 2.1: The major aspects of memory.......................................................................6
Figure 6.1: Distribution of age groups at point of randomisation (n=98)......................49
Figure 6.2: Distribution of educational levels at point of randomisation (n=98)...........49
Figure 6.3: Flow-chart depicting participant progression through phases of the
clinical trial.....................................................................................................................51
Figure 6.4: Profile plot showing the effects of Bacopa versus placebo for AVLT
trial a4.............................................................................................................................56
trial a5.............................................................................................................................56
trial a6.............................................................................................................................57
trial a7.............................................................................................................................57
total learning index ........................................................................................................58
retroactive interference index ........................................................................................58
List of Tables
Table 4.1: Summary of the clinical trials of neuropsychological effects of Bacopa.... 31
Table 6.1: Dependent variables at baseline: clinical characteristics and test scores at
point of randomisation (n=98), with analysis of group differences........ ..................... 45
Table 6.2: Significant effects of gender on task performance at baseline (n=98)..........46
Table 6.3: Significant effects of age on task performance at baseline (n=98) ..............47
Table 6.4: Correlation of length of education and task performance at baseline...........48
Table 6.5: Reasons for withdrawal from trial ............................................................... 50
Table 6.6: Total side-effects reported during study ......................................................52
Table 6.7: Mean (and SD) for all tasks by group and testing session........................... 54
Table 6.8: Significant group differences on primary outcome measures: results of
repeated measures analysis of variance......................................................................... 55
xii
1. INTRODUCTION
Some aspects of the function of memory decline throughout adulthood and into old age
as part of the normal ageing process. Many older people complain of memory
difficulties. As well as the memory loss of normal ageing, the pathological memory and
cognitive loss of dementia occurs in many older people. Dementia has a very high, and
increasing, incidence and prevalence. The escalation in dementia rates in an ageing
population poses great social, personal and economic problems for society. This trend is
observed in Australia and worldwide.
The exploration of potential therapies for improving cognitive function is thus an
important quest which could have enormous benefits for society. The greatest likelihood
of successful intervention lies with treatment at the earliest possible stages of dementia.
Both delayment and prevention of dementia onset would have a large impact in terms of
reducing both suffering and costs. There exists an unclear transitional phase between
normal age-related memory loss and the first manifestations of dementia. Mild
cognitive impairment (MCI) is one of the conditions recognised in this grey zone, and it
is an area of much research attention as it may represent a potential point of earliest
intervention.
Although many older people experience, and are troubled by, the memory difficulties of
normal ageing, no pharmacological therapies exist to address this problem.
Furthermore, the pharmacological therapies so far developed for the pathological
cognitive losses of dementia are highly inadequate in terms of both efficacy and side
effects. Thus there remains a serious gap in effective strategies for cognitive
improvement in both age related memory loss and dementia.
Bacopa monnieri is an ancient herbal remedy from the traditional Ayurvedic medical
system of India where it has been used and documented for many centuries to improve
mental health, intellect and memory. These traditional claims and usage have been
supported by clinical and laboratory studies in recent times, however there have been
only a small number of high quality clinical trials published to date, none of which have
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targeted older age groups. Thus the aim of this study is to see whether Bacopa monnieri
improves memory in healthy people over the age of fifty five years. The hypothesis to
be tested is that Bacopa will improve memory performance in older persons.
This study will thus help to determine whether Bacopa can offer benefit to older people
without dementia whose memory difficulties currently remain unaddressed, and thereby
provide an efficacious intervention where none currently exists. Furthermore, while this
study examines the effects of Bacopa on the memory performance of nondemented
older people, the findings may have implications for the dementia population, and
confirmation of the hypothesis would suggest that a clinical trial in subjects with
dementia or MCI would be warranted.
Many Australians look to complementary and alternative medicines (CAM) for
improvement in general health and cognitive function (Jorm et al., 2004; MacLennan et
al., 1996; Eisenberg et al., 1993). This study contributes to the evidence basis for CAM
usage and thereby helps to enable a more cost effective, efficacious and targeted usage
of these therapies, as well as potentially widening the pool of evidence based
therapeutic strategies for improvement of cognitive health.
To achieve the stated aim of this study, the early chapters review the literature in
relation to firstly, ageing-related memory changes, secondly, dementia and MCI, and
thirdly, Bacopa monnieri. Following on from the first introductory chapter, Chapter 2
gives an overview of the major aspects of memory and the effects that age related
change brings. This is discussed from the point of view of both neuropsychological
effects and also biological effects, that is, the effects of age on memory related aspects
of brain function and structure. Chapter 3 describes the problem and prevalence of
dementia in an ageing population and introduces the concept of MCI. This chapter
illustrates the importance of finding efficacious therapeutic interventions for these
conditions. Chapter 4 examines the literature on Bacopa monnieri, and provides the
rationale for exploring its potential as such an intervention.
Following on from the background chapters, Chapter 5 explains the methodology and
study design used and describes how a randomised, double-bind, placebo-controlled,
design is applied to answer the research question. Chapter 6 presents the results
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obtained from the trial, whilst Chapter 7 provides an in depth discussion and analysis of
these results, particularly the effects that Bacopa had on memory performance, the side
effects observed and how the findings relate to the previous literature. Arising from this
discussion chapter, the conclusion is presented in Chapter 8, which demonstrates how
the aim of the current study was achieved.
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2. MEMORY AND AGEING
2.1 Introduction
This chapter presents an overview and brief description of some of the basic concepts of
memory and cognition. Within this framework, the cognitive and memory changes that
frequently occur with normal ageing will be reviewed. Memory and the types of loss
that occurs in normal ageing are important concepts to elucidate because this provides a
context within which to view the current study’s exploration of Bacopa as a potentially
therapeutic agent for memory and cognitive improvement.
2.2 Cognition and memory - an overview
Human cognition can be divided into four main categories of functions:
reception/acquisition, memory/learning, thinking/reasoning, and expression/action
(Lezak et al., 2004:20). Memory is a major aspect of, and indeed is central to, all of
these cognitive functions. It is important to remember that in reality these functions are
not separate but are ‘inextricably bound’ and simply describe different aspects of the
same activity (ibid:20), and, also, that each of the functions may share many of the same
processing mechanisms (Craik & Jennings, 1992:53).
Memory may be defined as the learning, storage and retrieval of information (Kimmel,
1990:173). It has variously been explained and understood in terms of storage,
processes and systems depending on the perspective and orientation of the theoretician
(Craik & Jennings, 1992:52). These perspectives all divide memory into different
components- primary or short term and secondary or long term being two critical
distinctions.
Primary memory is the conscious awareness for an event or information that has only
just occurred and it lasts only a short while, (Carlson, 2002:370). A key feature of
primary memory is working memory (Baddeley, 1992) which involves temporary
storage, manipulation and transformation of information, and is required in every-day
cognitive tasks such as adding sums and making conversation. Indeed working memory
is involved in nearly all cognitive tasks (Reisberg, 1997:126). Three systems comprise
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working memory- two are ‘slave’ systems which store verbal and visual information,
and these are overseen by a ‘central executive’ system which controls attention, and
regulates, analyses and processes the incoming information. The central executive is a
function of the frontal lobe, and it is this aspect of working memory that is affected in
Alzheimer’s disease (Baddeley, 1991), and also by ageing processes (Van der Linden, et
al., 1994). Overall, however, age related deterioration in most primary memory tasks is
minimal (Balota, Dolan & Duchek, 2000:396).
Secondary memory, the system predominantly affected by ageing, refers to the longer
term storage of knowledge, which is no longer in conscious awareness but is available
for retrieval. It represents a huge repository of information which remains fairly stable
across time (Reisberg 1997:127). Secondary memory is further divided into declarative
(explicit) and non-declarative (implicit or procedural) aspects. These dual aspects of
long term memory were confirmed by studies of amnesic patients who maintained some
aspects of memory whilst losing others (Lezak et al., 2004:25).
Declarative memory is what is classically thought of when we speak of memory- it is
the long term memory of facts, figures, experiences and events available for conscious
retrieval- it refers to the ‘knowing that’ type of knowledge. Two sub-types of
declarative memory have been elucidated (Tulving, 1983): firstly, episodic- the memory
for specific events (and the source or context in which they occurred) and secondly,
semantic- the memory for general knowledge and facts. Episodic memory demonstrates
clear deficits in ageing (Craik & Jennings, 1992:96), which includes encoding, storage
and retrieval stages; and furthermore the source (or context) aspect of episodic memory
shows definite age-related impairment (Balota, Dolan & Duchek, 2000:395). Semantic
memory, by contrast, remains largely unaffected by age (ibid: 397).
Non-declarative (also called procedural or implicit) memory is not held in conscious
awareness but is automatic and includes skills and behaviours learned via repetition
(Craik & Jennings, 1992:54) - it is best understood as the ‘knowing how’ type of
knowledge. Examples of activities requiring the use of implicit memory are riding a
bicycle or playing an instrument. This aspect of long term memory is very durable and
weighty evidence exists to show that it is minimally affected by ageing (ibid: 94).
5
Figure 2-1 gives a framework of the major aspects of memory as discussed above. To
reiterate, it is evident that age related impairments are most pronounced in that aspect of
long term, declarative memory called episodic memory; whereas semantic and nondeclarative aspects of memory show little change with age. Primary (short term)
memory shows little deterioration with age, though aspects of working memory are
affected. Ageing related changes will be discussed in more depth in the following
section.
MEMORY
PRIMARY
(SHORT TERM)
WORKING MEMORY
SECONDARY
(LONG TERM)
DECLARATIVE
(EXPLICIT) ‘Know that’
NON-DECLARATIVE
(IMPLICIT) ‘Know how’
EPISODIC
SEMANTIC
Figure 2.1 The major aspects of memory
2.3 Memory and cognitive changes of normal ageing
Kral first classified the memory loss of normal ageing in 1962 by coining the term
‘benign senescent forgetfulness’ to differentiate it from pathological forms of memory
loss. Responding to the lack of specific diagnostic criteria in Kral’s definition, Crook et
al. (1986) presented classification and diagnostic criteria for ‘Age Associated Memory
Impairment’ (AAMI). This term was applied to the type of memory loss that occurs
with normal aging- specifically the memory loss of older people relative to their
younger years, but normal relative to their age group. It is defined by subjective
memory difficulties, performance on any well standardised memory test that is at least
one standard deviation below that of younger people, and occurring in people over 50
years of age, without any disease affecting memory or any intellectual deficit (ibid).
6
Hanninen (1996), in an extensive population study of AAMI, found that subjects were
impaired in both memory test performance as well as tests of executive functions
associated with frontal lobe function. This study also found AAMI to be unlikely to
progress to dementia, with only a slightly elevated incidence of dementia found in those
classified as having AAMI compared to other normal elderly. It is estimated that only
approximately one percent of those who experience AAMI will go on to develop
dementia, a figure similar to that found in the normal population (Small, 2002). AAMI
is an ambiguous entity, and its heterogeneous nature has led many researchers to
question its clinical usefulness.
Memory difficulties in the aged has a very high prevalence- reported as occurring in
almost half of the population over sixty-five years of age (Small, 2002). Subjective
memory complaints are thus a frequent phenomenon in older people, with community
studies demonstrating an incidence of such complaints in 25-50% of people in the over
65 year old age group (Kawas, 2003).
The mechanisms for normal age related memory loss are controversial, and not yet fully
elucidated (Christensen, 2001). Individuals vary greatly in memory performance and
this variability increases with age, pointing to the notion that there are a variety of
factors at play to create these cognitive changes (Kawas, 2003). Even though there are
many people whose cognitive performance remains intact with aging, it is most
common for aspects of cognition and memory performance to decline (American
Psychological Association, 1998) and Christensen concludes that cognitive changes are
inevitable- only the age of onset varies (2001). Longitudinal studies demonstrate this
gradual decline in memory and cognitive performance with ageing (De Carli, 2003;
Christensen, 2001), and it is clearly apparent in standardised memory tests where poorer
performance of older age groups compared to younger age groups is the norm (Anstey
& Low, 2004). Reflecting this, it is increasingly common for people to present to their
doctors with concerns about their memory and cognitive health (Small, 2002).
As well as the above-mentioned variance between individuals, variance within
individuals is marked in age related cognitive decline (Albert, 2002). Individuals vary
within themselves in that some memory and cognitive abilities decline faster than
7
others, i.e. the loss is not consistent across abilities (Christensen, 2001). The particular
aspects of memory that decline with age include aspects of long term, declarative
memory, aspects of working memory (both discussed above) and particularly, the speed
of cognitive processing, which shall be discussed below.
When researchers at the Mayo clinic investigated acquisition (learning) and delayed
recall (forgetting) in 161 normal elderly people, they concluded that a consistent and
gradual decline in acquisition occurs with age (Petersen et al., 1992). The decline in
acquisition is thought to be due to the slowing of processing speed rather than
capability- older people take longer to learn new information (Albert, 2002).
Acquisitional deficits may also reflect a decreased capacity to move information from
short term (primary) into long term (secondary memory) as reported by Craik &
Jennings (1992).
2.3.1 Speed of mental processing declines with ageing
Luszcz & Bryan (1999) in a thorough review of mediational theories of age related
cognitive change conclude that reduced speed of information processing is a
fundamental mediator of age related memory loss. This is in line with mediational
theories which purport the diminishment of overall cognitive functions (such as
executive processes and processing speed) rather than just isolated memory specific
processes (Sliwinski & Hofer, 1999). Slowing of mental processing speed with age has
been long apparent from the evidence of neuropsychological test performance
(Christensen, 2001), and has more recently been confirmed with brain imaging
techniques (Sachdev, 2001), which have been informing cognitive psychology since the
1990’s (Tulving, 2001:18).
Population studies also show that speed of mental processing declines with age,
although longitudinal studies show this is a milder effect than cross-sectional studies
have predicted (Kawas, 2003). Longitudinal studies are more realistic because they
show individual progression rather than group means (Christensen, 2001). Slowing of
processing speed may also be a factor in demonstrated age related declines in abstract
thought, visual and verbal memory and recall, naming and verbal fluency (Lezak et al.,
2004:297).
8
2.3.2 Fluid and crystallised cognitive abilities
In an attempt to differentiate those cognitive abilities affected by ageing from those
unaffected, the cognitive capacity of the brain has been categorised into two broad
types- these being crystallised and fluid abilities, initially expounded by Cattel in 1963.
Crystallised abilities come from accumulated knowledge- that accrued through learning,
life experience, education and culture (Anstey & Low, 2004). These types of functions
involve those cognitive abilities and skills which are familiar, well learned and well
practiced (Lezak et al., 2004:296; Christensen, 2001), hence crystallised abilities engage
long term memory (notably semantic and non-declarative aspects) (Anstey & Low,
2004).
Conversely, fluid intelligence requires new learning, finding solutions to unfamiliar
problems and reflects cognitive processing speed (Lezak et al., 2004: 296-7). It also
involves complex attention and working memory- all of which are effected by age
(Trollor & Valenzuela, 2001). Working memory shows age effects when mental
organisation or manipulation of material is required or when trying to remember
material whilst occupied with other activities (Lezak et al., 2004:298).
Fluid and crystallised abilities are thus affected very differently by ageing. Crystallised
abilities improve up into the 70’s age group with only slight decreases in very late old
age (Christensen, 2001), whereas fluid abilities diminish from young adulthood, with
accelerated decline after age 60 (Anstey & Low, 2004). Fluid abilities are affected by
environmental insults, genetics and the biological changes of ageing (ibid). This
decrease in fluid abilities occurs alongside structural and functional changes as
evidenced by neuroimaging techniques (Trollor & Valenzuela, 2001).
2.3.3 Biological changes of brain ageing
The ageing brain experiences structural and functional changes as well as biochemical
and molecular ones. In a thorough review Trollor and Valenzuela (2001) discuss some
of the biological changes that occur in the aged brain. After 40 years of age there is an
approximate reduction in brain size of 5% per decade (ibid). It is now known that this
atrophy is not attributable to neuronal loss as has classically been believed to be the case
9
(Horner & Gage, 2002). Recent neuron counting technology confirms that there is
minimal neuronal loss in normal aging except for that which occurs in specific regions
of the hippocampus; rather loss of size can be attributed to loss of synaptic connections
and dendrites, as well as reductions in white matter (Trollor and Valenzuela, 2001).
Age related changes in synaptic transmission result from structural and functional
changes in neural networks (Albert, 2002).
Brain atrophy shows a predilection for certain regions- particularly the prefrontal cortex
but also the neostriatum, midbrain and medial temporal areas (Trollor and Valenzuela,
2001). The decrease in hippocampal/medial temporal volume probably explains some
of the main ageing related memory deficits observed- those of declarative memory,
learning and spatial skills (ibid), as this region is critical in the formation of declarative
memory as well as visual and spatial memory (Zola & Squire, 2000:485-497).
Furthermore, degenerative changes in the neuronal circuits between the hippocampus
and key memory regions of the cortex occur (Albert, 2002).
White matter hyperintensities (WMH), viewed on magnetic resonance imaging (MRI),
can be present in up to 70% of normal aged brains by 70 years of age, and are
predominantly sub-cortical (O’Brien et al., 2003). Although researchers have
scrutinized these, their significance remains inconclusive at this point. They have been
correlated with decreased processing speed (Trollor & Valenzuela, 2001) and may be a
product of ischaemic brain changes as well as oxidative stress (O’Brien et al., 2003).
WMH have also been strongly associated with subjective memory complaints as well as
late-onset depression (Minett et al., 2005). As well as the occurrence of WMH, in the
aged brain more white matter than grey matter is lost; hence demyelisation may
contribute to age related diminishment of cognitive processing speed (Trollor &
Valenzuela, 2001).
It is known that β-amyloid plaques and neurofibrillary tangles (NFT) occur in normal
aged brains as well as Alzheimer’s disease (AD) (ibid). There are some differences
however- firstly, in normal ageing senile plaques are diffuse, in AD they are dense.
Secondly, NFT are not found in the cortex in normal ageing, whereas they are
widespread throughout the cortex in AD (ibid). The occurrence of these features in
normal brains is one of many factors leading some researchers to challenge the
10
hypothesis that they are pathological mediators of Alzheimer’s disease (AD). One
strong argument is that AD may be yet another cardiovascular pathology, with NFT’s
and plaques occurring as a result of ischaemic damage (de la Torre, 2004) in both
normal older and AD brain tissue.
Distinctive vascular changes occur in older brains- capillary density is reduced with
tortuosities and thickening occurring. By 40-50 years of age 50% of cerebral vessels
show thickening, increasing to 80% in the 80-90years age group (Klassen et al., 1968,
cited in Trollor & Valenzuela, 2001). Thus neurons in older brains may not receive
adequate oxygen and nutrition for healthy function, possibly leading to neuronal
dysfunction (Trollor & Valenzuela, 2001).
2.4 Healthy brain ageing
It is important to remember that not all older individuals undergo cognitive decline- it is
a common but not inevitable feature of advancing age (Kahn & Rowe, 1998). The fact
that some older people do not experience cognitive deterioration implies that it may be
preventable. The potential for plasticity (the capacity to generate more synaptic
connections) is maintained well into old age (Sachdev, 2001). It is now known that self
repair mechanisms exist and regeneration of neurones is feasible (Horner & Gage,
2002). This has implications that the brain may be able to benefit from brain restorative
tonics, as well as nutritional and other regenerative therapies.
2.5 Conclusion
To conclude, it is widely accepted that memory declines with age, but the exact nature
of the changes are still unknown despite widespread literature on the topic (Luszcz &
Bryan, 1999). However, it is known that different aspects of memory are affected
differently, and that cognitive ageing of individuals varies from person to person. It is
also agreed upon that speed of information processing is a central feature of age related
changes, and there is a decrease in long term declarative memory, acquisition, aspects of
working memory and fluid cognitive abilities.
Whilst acknowledging these declines in performance, it is important to remember that
the changes of normal ageing, unlike neuropathological changes, are mild and do not
interfere with a persons’ daily functioning. However, some cognitive deficits do occur
11
in most people with ageing and this is accompanied by biological changes in the brain.
Lastly, it is also important to bear in mind that not all older adults experience cognitive
deterioration and that the potential for brain plasticity exists. This implies that there may
be benefits to be had in therapeutic strategies aimed at improving brain function and
overall neurological health.
12
3. THE PROBLEM OF DEMENTIA
3.1 Introduction
This chapter features a discussion of the problem and prevalence of dementia in an
ageing populus which will clarify and justify the need for the development of
therapeutic strategies that can improve cognitive health, and potentially delay or prevent
dementia onset. This discussion highlights the need for, and benefits to be had by,
effective early intervention strategies for dementia.
Secondly, the concept of transitional cognitive impairment states that lie on the
continuum between normal, ageing-related cognitive decline and the pathological
cognitive loss of dementia will be introduced. In this context, there is a particular focus
on mild cognitive impairment (MCI), as, in many people, this condition represents the
earliest signal of approaching dementia, and hence a time of potential early intervention.
3.2 Demographic background: an ageing populace
In Australia’s early history (and worldwide), infectious disease was the biggest killer.
When public health improvements and later, antibiotics reduced infection rates, then
mortality from infectious disease decreased markedly, and cardiovascular disease
(CVD) and cancer emerged as the leading causes of morbidity and mortality (Jorm,
2001). Since prevention and treatment strategies for CVD and cancer have progressed,
people now have a longer life expectancy (ibid.). Coupled with longer life expectancy is
the ageing of the post-World War II cohort. As this so-called ‘baby-boomer’ generation
ages, Australia will increasingly experience a ‘boom’ in the older age groups, especially
the ‘old-old’ age group (those over 85years) - in fact this age group is the most rapidly
increasing section of the population (Jorm, 2001). This phenomenon of an ageing
population is not expected to ease until the 2040’s when cohorts from lower birth rate
periods will constitute the older age groups.
Degenerative neurological conditions typically become evident in later life. Hence
neurological illness is emerging in epidemic proportions and constitutes a threat to
public health care resources as well as to the wellbeing and quality of life of older
13
Australians. One might also ponder the increased risk of neurological damage that the
baby boomer generation might be prone to due to widespread psychotropic recreational
drug exposure, as well as ever increasing environmental xenobiotic exposure which has
neurotoxic effects and causes deleterious effects on cognitive performance (for example
Ganzevles & de Geus, 1991; Mearns et al., 1994).
3.3 Dementia prevalence and cost
It is in the ‘old-old’ that neurodegenerative disease and especially dementia has the
highest prevalence, for example, it is estimated that one in twenty Australians over 65
years old (Australian Department of Health and Aged Care, 1999) and almost one in
four over 85 years old have dementia (23.6% in 1995), (Henderson & Jorm, 1998:12).
For every 5.1 years of life after age 65, dementia prevalence doubles (Jorm et al., 1987).
This reflects a high incidence rate: currently, approximately 1000 Australians are
diagnosed with dementia every week (CSIRO, 2005).
The future outlook does not get brighter- dementia prevalence rates are expected to
swell enormously. The increase in dementia will far outstrip the increase in the
Australian population in the coming decades. Current figures are far from reassuringHenderson and Jorm (1998:15) calculate that while the total Australian population will
increase by 40% in the years 1995-2041, the number of dementia cases will increase by
254%, explained by the aforementioned disproportionate increase in the old-old. Hence,
dementia not only causes immense distress to sufferers and their families, but poses
major social and economic problems for society at large.
On an economic level, the costs associated with this burgeoning neurodegenerative
disease epidemic are enormous and will increase. Because dementia causes chronic,
severe, progressive disablement of people over a long period, it has very high care costs.
A recent report by the Australian Institute of Health and Welfare (AIHW) identified
dementia as the greatest cause of disease burden due to disability in the elderly as well
as the largest source of expenditure in residential aged care (2004: xi). Dementia cost
the Australian health and aged care systems just over 2.5 billion dollars in 2000-01,
with 84% of this cost being expenditure on residential aged care (ibid: 75).
14
This issue of the increasing prevalence and cost of neurodegenerative disease is not
unique to Australia, it is a worldwide phenomenon. Research based on global
demographic data approximates that 25 million people had dementia in 2000, which is
expected to rise to 63 million by 2030, with the majority of cases occurring in less
developed regions of the world (Wimo et al., 2003). The most promising way of
potentially avoiding such increases in dementia prevalence and cost will be the
development of therapeutic strategies to delay, prevent and/or treat it (AIHW, 2004).
3.4 Dementia pathologies
Dementia is not a disease but is a syndrome of progressive cognitive decline caused by
numerous different pathologies- in fact it is estimated that more than 200 types of
dementia exist (Haan & Wallace, 2004). In early stages cognitive symptomatology
differs with different aetiologies, however as neurodegenerative pathology progresses,
then the marked destruction of brain tissue renders similar symptoms whatever the
cause (Lezak et al., 2004:207).
The various pathological mediators of dementia include Alzheimer’s disease (AD),
vascular dementia (and mixed forms of both of these), Lewy body dementia, Picks
disease, Huntington’s disease, Parkinson’s disease, substance-induced dementia, head
trauma, as well as various immune, endocrine, and systemic disorders amongst others
(American Psychiatric Association, 2000:147-171). Of these, AD and vascular dementia
account for the vast majority of cases.
AD is the major cause of dementia, accounting for an estimated 50-70% of cases,
whereas vascular dementia accounts for 20-30% (Alzheimer’s Australia, 2004). AD is a
chronic degenerative condition that causes changes in structure and function of the
brain. Cell numbers are diminished in specific areas of the brain, including the frontal,
temporal and parietal cortex and the hippocampus. Neuritic plaques of β-amyloid and
tau protein composition and neurofibrillary tangles form in the brain tissue throughout
the cortex and sub-cortical grey matter. There occurs a depletion of the neurotransmitter
acetylcholine and the enzyme which produces it- choline acetyltransferase, along with
other neurotransmitters and neurochemicals (World Health Organisation, 1992, cited in
Henderson & Jorm, 1998). These changes result in diminished cognitive function that
worsens as the disease progresses.
15
The cognitive changes associated with dementia generally progress along a continuum
from normality to mild, moderate and severe stages, though there are wide variations of
symptoms and progression between individuals. Abrams, Beers and Berkow (1995)
describe these cognitive changes as follows. There is impairment in short term and long
term memory, particularly the inability to learn and recall new information. Problems
with abstract thinking and judgement occur, as well as the loss of higher cortical
functions causing language difficulties, motor impairments, problems with recognition,
and personality changes. Eventually, neurological destruction affects all bodily systems,
and people generally die of illnesses of debility such as pneumonia (Lezak et al.,
2004:207).
3.5 Therapeutic strategies for dementia
Unfortunately there are no effective medications available for Alzheimer’s disease or
dementia. The anti-psychotic drugs frequently applied to manage the behavioural
symptoms ironically can cause neurological side effects and excessive sedation
(Bennett, 1999). One must question the effects of these strong drugs on an already
confused mind. One longitudinal study found that these medications doubled the rate of
cognitive decline in AD (McShane et al., 1997). A data survey of Sydney nursing home
residents found 27.4% were on regular anti-psychotic medication, mainly those
residents with greatest cognitive impairment (Snowdon et al., 1995). The widespread
use of these drugs may help make the patient with dementia a little more controllable
(for example see Phipps, 1999), but the cost is further impaired cognitive function.
Specific pharmacotherapies developed for Alzheimer’s’ disease, such as tacrine,
donepezil, rivastigmine and galantamine, inhibit cholinesterase- the enzyme that breaks
down acetylcholine. Studies (for example, Knapp et al., 1994; Rogers et al., 1998;
Courtney et al., 2004) have shown these agents do have modest clinical efficacy, but
they do not effect the underlying pathology and this, coupled with strong side effects,
results in questionable usefulness. There is evidence that these medications can slow the
progression of symptoms initially, but don’t change the overall outcome or prognosis
(Lopez, et al., 2002). The search for effective therapeutic strategies continues.
16
As Jorm (2002) points out, disease prevention can mean either elimination or
postponement until later life, the latter being a more probable prospect for dementia.
The development of therapies that can delay the onset of dementia, by even moderate
degrees, could have an enormous favourable impact on both public health expenditure
and personal suffering (Alzheimer’s Australia, 2004). For example, Access Economics,
in a study commissioned by the Alzheimer’s Association Australia, determined that if,
starting in 2005, the age of onset of Alzheimer’s disease could be delayed by just 5
months, there would be 5% less new cases per year, and if delayed by 5 years there
would be 50% less new cases per year (Access Economics, 2004: i). Furthermore, these
researchers demonstrate that a 5-year delayment would cumulatively save the Australian
economy many billions of dollars (67.5 billion dollars by 2040).
The staggering prevalence figures and the reductions in costs and suffering that
effective interventions could produce indicate the urgent need for preventive and
disease delay tactics. Scarpini et al. (2003) identify three promising areas of research:
firstly, reduction of risk factors- such as oxidative stress, cardiovascular risk factors and
inflammation; secondly, neurogenesis promotion- via stem cell and nerve growth
factors and lastly, prevention and removal of amyloid plaque via vaccine and chelation
agents.
In the category of reduction of risk factors, much promising work exists to suggest that
prevention of AD is possible (Mattson, 2000). It is in the area of risk prevention that
both nutritional approaches and botanical medicines may have a lot to offer. It is
becoming widely recognised that reduction of cardiovascular risk factors will also
decrease the risk of dementia of both AD and vascular types. Specifically, these factors
include elevated homocysteine and LDL cholesterol levels, obesity, hypertension and
diabetes mellitus- all of which are modifiable (Haan & Wallace, 2004; Mattson, 2000).
Dietary consumption of fish, monounsaturated oils and antioxidants have all been
associated with lowered risk for dementia (Morris et al., 2005; Barberger-Gateau et al.,
2002; Solfrizzi et al., 1999; Morris et al., 2002) as has caloric restriction (Mattson,
2003). As well as dietary antioxidants, research also supports a role for supplemental
antioxidants, especially vitamins C and E, in dementia prevention (Larrieu et al., 2004;
Zandi et al., 2004; Sano et al., 1997).
17
Plant medicines that reputedly act to improve function of the central nervous system are
a promising area for research. They are most likely to offer benefits in the
abovementioned ‘reduction of risk factors’ category of therapy, because many
phytochemicals from plants are now known to be powerful antioxidants, and many also
have antiinflammatory actions. Bacopa has been shown to possess both of these actions
(Bhattacharya et al., 2000; Tripathi et al., 1996; Russo et al., 2003a; 2003b; Jain et al.,
1994). Furthermore, Bacopa has also been shown to possess a cholinergic modulation
effect (Bhattacharya et al., 1999). This is a significant effect because, as highlighted
earlier, cholinergic deficits are a feature of dementia (World Health Organisation, 1992,
cited in Henderson & Jorm, 1998).
Other indications that promising therapeutic agents might be found in the plant kingdom
come from studies wherein various herbs have demonstrated beneficial cognitive and
neurological effects. For example, many well designed trials have shown the positive
effect of Gingko biloba extract on dementia. Between 1975 and 1992 there were 34
clinical trials of Gingko involving 2326 patients, in which the incidence of side-effects
was below 3% (Schulz et al., 1997). Improvements in mental speed, memory and
concentration (Vesper & Hansgen 1994), cerebral perfusion (Kleijnen & Knipschild
1992), and overall cognitive function (Hofferberth, 1994) have been well demonstrated.
One high quality 12-month RDBPC clinical trial found Gingko improved cognitive
symptoms in dementia to a degree equivalent to the acetylcholinesterase inhibitor
medications, with an absence of adverse effects (Le Bars et al., 1997).
Panax ginseng is another example of a plant which has demonstrated promising
neurological benefits. Blumenthal reviews a number of human studies which have
demonstrated improvement in various cognitive and psychological parameters with
Panax administration (2003:215-225). Thus the beneficial neurological effect of some
botanical agents has been well demonstrated and this supports the exploration of
Bacopa monnieri as another potentially therapeutic botanical agent.
3.6 Pre-clinical dementia states
Dementia is not a natural consequence of the ageing process. People experience varying
degrees of cognitive deterioration as they age- from nil in some cases of so called
‘successful ageing’ (Kahn & Rowe, 1998), through to the pathological loss of dementia.
18
Between normal ageing-related cognitive change and the pathological changes of
dementia, lies a transitional zone of cognitive impairment, wherein there may be some
loss of cognitive function of various manifestations and aetiologies, which is not severe
enough to affect daily functioning, but will progress to dementia in some cases. The
pathology of Alzheimer’s disease can be present for many years before it is diagnosed,
and its earliest stages may exhibit only subtle cognitive changes (Alzheimer’s Australia,
2004:11), hence this transitional zone may represent the earliest stages of dementia for
many people. Therefore, this has become an area of research focus in the attempt to
enable researchers to ultimately address dementia at its earliest stages by developing
strategies to treat, prevent or delay its onset (Albert, 2002).
In the literature, a number of different terms have been developed to describe various
states of slight cognitive impairment. These include (amongst others): age-associated
cognitive decline (AACD) (Levy, 1994), cognitive impairment no dementia (CIND)
(Graham et al., 1997) and mild cognitive impairment (MCI) (Petersen et al., 1999).
Unsatisfactory boundaries exist between the various syndromes, resulting in a confusing
overlap between aetiology, prognosis and prevalence (De Carli, 2003). However,
despite the fact that definite and unanimous criteria have not been fully established for
any of these classifications, MCI is widely gaining acceptance as a meaningful defining
concept, and it has been further refined over the years to provide better diagnostic and
operational criteria, including the elucidation of sub-types (Petersen, 2004).
Mild Cognitive Impairment (MCI) describes people who have cognitive impairment
beyond that of normal ageing but are not demented. Unlike normal age-related changes,
however, MCI is recognised as a pathological entity (Petersen, 2004). The criteria for
MCI include memory complaints with preserved intellectual and daily functioning,
impaired memory relative to peers and the absence of dementia (Petersen et al., 2001).
The usefulness of its operational criteria in distinguishing between normality and
dementia has been demonstrated in a descriptive and comparative study of participants
with MCI enrolled in a large multicentre clinical trial (Grundman et al., 2004).
MCI has been classified into various sub-types, some of which are now recognised as
prodromal forms of various dementia types- however specific criteria are yet to be
agreed upon (Petersen, 2004). The sub-types include amnestic MCI (a-MCI) wherein
19
memory is objectively and subjectively impaired, but daily functioning and other
cognitive domains are preserved; multiple domain MCI (md-MCI) which describes
multiple cognitive impairments of varying degrees with or without memory problems;
and lastly a single domain non-memory MCI (such as language for example), which is
uncommon (Petersen et al., 2001). Each of these sub-types exhibits a propensity to
develop into different dementia types, with a-MCI particularly indicative of possible
future AD.
From a longitudinal study of 220 older people from the Mayo Alzheimer’s Disease
Research Centre, researchers estimated that approximately 12% of people with MCI
progress to dementia annually (in contrast to approximately 1-2% of the general
population), and that if followed for 6 years, 80% will have become demented (Petersen
et al., 1999; 2004). However, in the literature there is a large variation in reports of rates
of progression to dementia and this probably reflects differences in subjects, diagnostic
criteria used, as well as varying lengths of follow up (Dawe et al., 1992). Likewise,
estimates of the prevalence and incidence rates of MCI vary widely depending on the
diagnostic criteria used (Busse et al., 2003). It is widely agreed upon though, that MCI
occurs frequently in the aged population (ibid.), and people with it are at greater risk
than the normal population of developing dementia, even though the degree of risk has
not yet been established (Schneider, 2005). Hence MCI represents a potential area for
early dementia intervention strategies.
3.7 Conclusion
The Australian population, following the global trend, is experiencing an ageing
population, with particular increases in the ‘old-old’. It is in this age group that
neurological illness occurs most frequently, and of the neurological illnesses dementia
is the most prevalent. Hence there is a burgeoning epidemic of dementia. This is
associated with huge costs in terms of both personal suffering and economics. Effective
pharmacological therapies do not currently exist, and remain elusive. Botanical agents
have shown some benefits in improving neurological health, and lifestyle, nutritional
and cardiovascular risk reduction strategies appear to offer very promising outcomes for
dementia risk reduction and prevention. Even small delays in dementia onset would
have enormous benefits. The development of such strategies is imperative.
20
A more marked impairment of cognition and memory than occurs in normal ageing
becomes apparent in some older people, and there is a recognised transitional zone
between normal ageing and dementia. Various terms have been applied to this state,
with MCI now recognised as a possible manifestation of very early dementia. Much
attention has been focused on this area because early diagnosis and intervention present
the greatest hope and potential for achieving prevention, delay and treatment strategies
for dementia. Restoration of brain health and cognitive function is one of the most
promising areas for potentially reducing the incidence and hence prevalence rates of
dementia and thereby alleviation of suffering and costs.
21
4: BACOPA MONNIERI
4.1 Introduction
Much has been written over the ages about Bacopa monnieri (Bacopa). As this research
project sought to observe the effects of Bacopa on the memory of older people in a
randomised controlled clinical trial, a detailed analysis of what is currently known about
the herb is required. This chapter will therefore examine what is known about Bacopa
including its historical and contemporary application, its constituents and its known
effects.
The knowledge gleaned from the traditional usage of plant medicines globally can point
to therapeutic agents which potentially have a lot to offer modern health care practice,
and this may be especially relevant for pathologies where effective pharmacological
therapies are unavailable or inadequate. Impaired cognition in the aged is a condition for
which there is a paucity of effective therapies, and additionally, it presents a large and
escalating public health issue.
A plant that has been shown, in the literature explored below, to hold great promise for
the improvement of cognitive function is Bacopa monnieri, commonly called Brahmi in
Sanskrit and in Hindi, and water hyssop in English. Bacopa belongs to the family
Scrophulariaceae, and is a small succulent creeper that thrives in warm climates
throughout the world, growing in moist places and along waterways. It is a plant that is
native to both India and Australia. Bacopa’s botanical name has numerous synonyms,
commonly encountered ones include: Bacopa monniera Wettst., Bacopa monniera
Linn., and Herpestis monniera (Kapoor, 1990; Morgan & Bone, 1999; Russo & Borrelli,
2005).
4.2 History
Bacopa has been regarded as a highly effective brain tonic since antiquity in the
Ayurvedic medical system of India (Singh & Dhawan, 1997). According to Hackman
(1998), early Hindu religious practices prior to written history required the
memorisation and repetition of lengthy, orally transmitted Vedic scriptures by scholars.
22
Bacopa was reputedly used in these early times to enhance the scholars’ capacity to
memorise these epic hymns and scriptures (ibid.).
The herb has been described in Ayurvedic texts since around 800 BC and recorded as a
treatment for a range of mental disorders in the ‘Carak Samhita’ (Singh & Dhawan,
1997), which, according to the literature, was written in the 6th century AD (Chowdhuri
et al., 2002; Russo & Borrelli, 2005). In a later treatise of the 16th century, the
Bhavprakasa Varg-Prakarana, Bacopa’s actions are set down as follows: bitter, laxative,
astringent, brain tonic, memory enhancing, and longevity promoting. As well as brain
conditions such as epilepsy, insanity and neuroses, other indications described in this
treatise include anaemia, leprosy, renal disease, blood disease, poisoning and cough
(Singh & Dhawan, 1982).
Ayurvedic medicine classifies Bacopa as belonging to a group of plant medicinesknown as medhya rasayana- that improve mental health, intellect and memory (medhya)
and promote longevity and rejuvenation (rasayana) (Singh & Singh, 1980). The Sanskrit
name Brahmi stems from Brahma- the creative aspect of God. As the brain is seen as
the creative centre of humans, then Bacopa, which acts primarily on the brain, is so
named (Russo & Borrelli, 2005). Hence Bacopa shares its Sanskrit name, Brahmi, with
another herbal nervous system restorative- Centella asiatica (Gotu kola) (Morgan &
Bone, 1999).
4.3 Constituents
Many of Bacopa’s constituents have been identified including numerous saponins,
alkaloids designated Brahmine and Herpestine, and flavonoids. In a thorough review of
the chemical composition of Brahmi, Russo and Borrelli (2005) point out that the first
constituent identified was an alkaloid ‘Brahmine’ in early work by Bose and Bose
(1931). Alkaloids have been found to have only a poor yield, however (Dey et al.,
1964). In the 1950s and 60s research by chemists at India’s Central Drug Research
Institute identified a variety of saponins, and the elucidation of constituents by various
laboratories is still continuing. For example, bacopasides I to V have been identified,
and also bacopasaponins A to G, as well as bacosides A1 to A3 and B. (Chakravarty et
al., 2001, 2003; Hou et al., 2002; Mahato et al., 2000; Rastogi et al., 1994). Saponins
are considered to be the major active constituents of the plant.
23
Saponins are glycosides, a sugar unit attached to an aglycone portion (the sapogenin).
The sapogenin portion describes the type of saponin- either steroidal (4-ringed
structure), or triterpenoid (5-ringed structure) (Mills & Bone, 2000:43). The main active
chemical constituents of Bacopa are the dammarane-type triterpenoid saponins (Garai et
al., 1996a, 1996b; Mahato et al., 2000) with jujubogenin and pseudojujubogenin as the
aglycones (Deepak & Amit, 2004). The saponins consist of numerous subtypes
designated as bacosides, bacopasides and bacopasaponins as mentioned above.
Bacoside A is considered the major active component, first identified by Chatterji et al.
in 1963, with bacoside B being an optical isomer of A (Singh et al., 1988). Morgan &
Bone stated in 1999 that in herbal extracts standardised to bacoside A content, it is
likely that bacoside A collectively refers to the overall content of dammarane saponins
rather than a solitary saponin. This view is supported by a 1978 study that had shown
bacoside A to be a mixture rather than a single saponin (Kawai & Shibata). A recent
study has confirmed this by identifying four major components of bacoside A, these
being: bacoside A3, bacopaside II, bacopasaponin C and the jujubogenin isomer of
bacopasaponin C. The authors who identified these components also reported the
presence of two well known flavonoids: luteolin and apigenin in all samples (Deepak et
al., 2005).
It is significant that dammarane-type saponins are also the primary active constituents in
Panax ginseng (Blumenthal, 2003:215), in which they have been shown to promote
memory acquisition, retention and retrieval in rats (Ma & Yu, 1993; Ma, Yu & Chen,
1991) and survival of experimentally damaged neurones in chicken and rat cerebral
cortex (Himi et al., 1989).
4.4 Pre-clinical and clinical studies of the cognitive effects of
Bacopa
4.4.1 In vitro and animal studies
Learning ability in rats has been significantly enhanced by Bacopa extract as it
facilitated acquisition, consolidation and retention of three newly learned behavioural
responses at an oral dosage of 40mg/kg three times daily (Singh & Dhawan, 1982). In
24
this study, effects on cognitive function were measured by foot shock motivated
brightness discrimination reaction, active conditioned flight reaction (jump to avoid
shock) and continuous avoidance response (shock avoidance by lever pulling) tests.
Bacopa facilitated all parameters of memory acquisition and retention.
In a subsequent study the same authors investigated the constituents responsible for
Bacopa’s effect and demonstrated that the isolated bacosides A and B were effective in
enhancing memory in rats in learning tasks involving both positive and negative
reinforcement (Singh & Dhawan, 1997; Singh et al., 1988). Additionally, this study
demonstrated that the bacosides produced changes in the hippocampus, cerebral cortex
(areas critical to memory function) and hypothalamus regions of the brain and caused
enhanced levels of protein kinase activity and increases in protein levels in these
regions. This indicated positive implications for improved neurotransmission and repair
of damaged neurons via enhanced regeneration of nerve synapses (Singh & Dhawan,
1997).
A recent study concurs with Singh and Dhawan’s findings regarding the effects of
isolated Bacopa saponins on memory. Administration of bacosides to mice attenuated
experimentally induced anterograde amnesia and improved memory as measured by a
well validated learning task- the Morris Water maze test (Kishore & Singh, 2005).
4.4.1.1 Cholinergic effects
The diminished ability to learn and recall new information is a strong feature of
Alzheimer’s disease. In rat models of Alzheimer’s disease, Bacopa was shown to
significantly promote memory as well as reversing induced reductions of acetylcholine
(ACh) in the frontal cortex and hippocampus regions. The activity of choline
acetyltransferase (ChAT- a key catalyst in the production of ACh), and muscarinic
receptor binding of ACh were also improved (Bhattacharya, Kumar & Ghosal, 1999).
ACh is a neurotransmitter which plays an important role in memory and learning
functions in the cerebral cortex and the hippocampus (Carlson, 2002:106). Furthermore,
depletion of ChAT and hence ACh, is one of the central neuropathological features of
Alzheimer’s disease (World Health Organisation, 1992, cited in Henderson & Jorm,
1998). Bhattacharya et al. (1999), demonstrated that the mechanism of action of Bacopa
is likely to be, at least in part, related to cholinergic modulation.
25
Further support for a cholinergic effect of Bacopa comes from two other animal studies.
Firstly, Das and colleagues (2002) demonstrated an in-vitro, dose dependent, partial
inhibition of the activity of acetylcholinesterase (AChE- the post-synaptic enzyme
which breaks down ACh), as well as significantly attenuated cognitive performance
observed in-vivo in rats with scopolamine-induced dementia. Secondly, an early study
by Dey et al. (1964) demonstrated hypotensive and bradycardic effects in cats with
administration of intravenous Bacopa, leading these researchers to postulate that the
mechanism was via cholinergic activation because the effect was partly (60-70%)
blocked by atropine, (atropine blocks muscarinic ACh receptors).
4.4.1.2 Antioxidant activity
The antioxidant activity of Bacopa has been reported in a number of laboratory studies
(Tripathi et al., 1996; Bhattacharya et al., 2000; Sairam et al., 2001; Sumathy et al.,
2001, 2002; Russo et al., 2003a, 2003b). Antioxidant effects of Bacopa in areas of the
brain that are key memory areas- the hippocampus, frontal cortex and striatum- have
been documented by Bhattacharya et al. (2000) in rat brain. Bacopa was shown to
protect the brain (Sumathy et al., 2002) and liver (Sumathy et al., 2001), from
morphine-induced inhibition of antioxidant enzyme systems. Russo et al. (2005)
demonstrated a free radical scavenging activity which protected against cytotoxicity and
DNA damage in human fibroblasts (Russo, et al., 2003a). Further research by Russo et
al. (2003b), also demonstrated that Bacopa significantly reduced oxidation and DNA
damage in cultured rat astrocytes induced by a nitric oxide donor. Furthermore,
Anbarasi et al. (2005) demonstrated that isolated bacoside A protected rat brain tissue
from various parameters of oxidative stress caused by chronic cigarette smoke exposure.
One of the foremost theories of brain ageing asserts that free radical damage results in
both ageing-related changes in healthy brains (Trollor & Valenzuela, 2001) and in
neurodegenerative pathology, such as Alzheimer’s disease (Singh, et al., 2004). Good
antioxidant status is associated with better memory performance in the aged (Perrig,
1987) and antioxidant therapy has been targeted as a promising dementia strategy by
Jorm, one of Australia’s foremost authorities on dementia (Jorm, 2002). Thus, the
demonstrated antioxidant effects of Bacopa, particularly in brain tissue, support its
26
potential as a therapy in neurodegenerative pathologies and age-related cognitive
decline.
Stress elicits a defensive response in living organisms. The defence response involves
several mechanisms including stress gene expression, enhanced antioxidant protection,
and enhanced toxin clearance. Bacopa has been shown to facilitate each of these
adaptive resources by modulation of Hsp 70 expression, and enhancement of activity of
both superoxide dismutase and cytochrome P450 enzymes in stressor exposed rat brain
(Chowdhuri et al., 2002). Thus, Bacopa may facilitate the capacity of the brain to
withstand stress, and help the brain to function under adverse conditions.
These findings support the afore-mentioned medhya rasayana classification of Bacopa
in ancient Ayurveda in that they imply a brain tonic and adaptogenic effect (adaptogenic
meaning improved resistance to stress). This may indicate some similarities with Panax
ginseng (another dammarane saponin-containing herb as mentioned previously), which
is considered to be a major adaptogen and tonic, enhancing resistance to stress in
numerous experimental situations as well as clinical trials (Blumenthal, 2003: 214-226;
Mills & Bone 2000:420-427).
4.4.2 Human trials
In the clinical trials described below, Bacopa has been found to improve various aspects
of cognitive function in children and adults. Sharma et al. (1987) found that learning,
memory, perception and reaction times improved in 20 primary school children given
Bacopa in syrup form at a dosage of 350mg three times daily for three months. No side
effects were reported. This study was strengthened by the use of a matched placebo
control group (n=20). However, the study was limited in that it was not double-blinded,
and used a small sample size.
Negi et al. (2000) reported children with attention deficit hyperactivity disorder
(ADHD) were found to benefit from Bacopa administration. A randomised, doubleblind, placebo-controlled trial of 36 children with ADHD was carried out by the Indian
researchers. Bacopa was given at a dosage of 50mg twice daily for 12-weeks, and a
battery of cognitive function tests administered at baseline, 4, 8, 12 and 16-weeks (i.e.
4-weeks post trial). Improvements were reported in the active treatment group (n=19) at
27
12-weeks, as measured by tests of sentence repetition, logical memory, and paired
associate learning tasks. Interestingly, improvement was still apparent at 16-weeks, four
weeks after cessation of Bacopa administration.
In an open trial, 35 adults with anxiety neurosis were treated with Bacopa at the dose of
12g of dried herb daily in syrup form for 4-weeks. No significant side effects were
observed and results were highly favourable as overall anxiety levels, concentration and
memory span were all significantly improved along with other major anxiety-related
physical symptoms and biochemical markers of anxiety (Singh & Singh, 1980). Whilst
the findings of this study are encouraging, the lack of a control group is a significant
design flaw, and further, the researchers do not delineate the selection criteria for
inclusion in the study.
Bacopa’s anxiolytic action was supported in a later animal study in which it was
compared with a major pharmacological anxiolytic agent- the benzodiazepine
lorazepam, in validated rat models of anxiety. It proved to be as effectual as the drug in
every outcome measured without producing any motor deficits (a common side-effect
of lorazepam) (Bhattacharya & Ghosal 1998). Whilst promising, these findings indicate
the need for further rigorous clinical trials to establish whether they are applicable to
humans. It is noteworthy that support for an anxiolytic action in humans was provided
by a well designed clinical trial (discussed below in detail) in which state anxiety was
significantly improved by Bacopa (Stough et al., 2001).
Some recent Australian studies demonstrate that Bacopa may be effective for enhancing
cognition in longer rather than shorter term administration. One study, using a
randomised, double-blind, placebo-controlled design, tested the effects of Bacopa
monnieri on cognitive function in forty six healthy adults between 18-60years of age.
Participants took Bacopa (300mg daily) or placebo for 12-weeks and measurements,
using a battery of well validated neuropsychological tests, were recorded at baseline, 5weeks and 12-weeks. Significant improvements were found in the active treatment
group in speed of information processing (as measured by the Inspection Time task),
learning rate and memory consolidation (as measured by the Rey Auditory Verbal
Learning Test) and state anxiety levels (as measured by Spielberger’s State Anxiety
Inventory). Improvements were only found at 12-weeks and not earlier, suggesting that
28
chronic administration is required to elicit Bacopa’s effects (Stough et al., 2001). This
study is well designed and rigorous; however, a limitation is that it does not take into
account age, gender or education effects, all of which are known to effect performance
on memory tests.
In contrast to the findings of Stough et al., members of the same research team reported
that Bacopa had no acute effect on memory, when outcomes were measured at 2-hours
post-administration (Nathan et al., 2001). In this study a randomised, double-blind,
placebo-controlled trial was used to assess the acute effects of Bacopa (300mg daily) on
thirty eight healthy adults between 18-60 years of age. The same well validated
neuropsychological test battery as employed in the Stough study (above) was used to
assess the effects of Bacopa before and then 2-hours after administration. No effects
were found.
Additionally, in a later randomised, double-blind, placebo-controlled study of 85 adults
(aged 19-68years) which tested cognitive effects of a combined tablet of 300mg Bacopa
with 120mg Gingko biloba, no significant effects were found in outcomes measured at
2-weeks and 4-weeks of treatment duration (Nathan, et al., 2004). Despite extensive
searching of the literature it appears that the effects of Bacopa observed at 12-weeks
have not been reported for lesser durations in well designed, larger human trials.
Another Australian based randomised, double-blind, placebo-controlled study
confirmed the efficacy of Bacopa in improving memory in chronic administration. In
this study, seventy six adults 40-65years of age, were given Bacopa (dose 300mg, or
450mg for persons over 90kg) or placebo and measured on tasks of attention, memory
and psychological state at baseline, 12-weeks and 6-weeks post trial (Roodenrys et al.,
2002). Bacopa significantly improved the ability to retain information over time as
measured by a task requiring delayed recall of word pairs. The authors commented that
this may be due to less information being lost from memory, that is, the results are due
to decreased forgetting, as opposed to enhanced acquisition because learning trials did
not show any effect of Bacopa. Outcome measures in this study which failed to show a
significant effect for Bacopa were tasks of short term memory, working memory,
attention, retrieval of prior knowledge and psychological state (anxiety, stress and
depression).
29
Roodenrys et al.’s finding of decreased forgetting rate as measured by a word pairs task
supports the aforementioned findings of Stough et al. (2001) who also reported
decreased forgetting rate, as measured by the AVLT. In contrast to Roodenrys et al.,
however, Stough’s study, as well as the animal study of Singh and Dhawan (1997), did
find an improvement in learning rate. A further contrast between the two studies is
Stough et al’s finding of Bacopa’s efficacy in reducing anxiety. Additionally,
Roodenrys et al.’s findings also contrasts with the anxiolytic effect observed in
aforementioned studies by Singh & Singh (1980) and Bhattacharya & Ghosal (1998).
The Roodenrys et al. study demonstrates a sturdy design, using well validated
instruments to measure outcomes; however as in the Stough et al. study, age and
education were not controlled for nor were the data adjusted for the effects of multiple
measures. Thus there is an increased chance of a type one error. The clinical trials on
the neuropsychological effects of Bacopa are summarised in Table 4.1.
A double-blind, placebo-controlled toxicological study in which bacosides were
administered in various single doses (ranging from 20mg to 300mg) as well as multiple
doses (100mg and 200mg) to healthy male volunteers for one month demonstrated an
absence of any side-effects (Singh & Dhawan, 1997). The herb is TGA approved in
Australia for over the counter sale as it is considered safe, and no adverse reactions are
recorded in the literature. The traditional recommended dosage regimen is 5-10g of the
powdered dried herb daily (Anonymous, Indian Herbal Pharmacopoeia, 2002:36).
30
Table 4.1: Summary of the clinical trials of neuropsychological effects of Bacopa
Author and Design
Year
Nathan
R, DB, PC
et al., 2004
n=85
healthy adults
aged 19-68yrs
Dosage and Duration
Results
Combination of
Bacopa 300mg/day and
Gingko 120mg/day
4-weeks
Measurements at baseline, 2 &
4-weeks. No significant effect
found on cognition and
memory. No difference in sideeffects compared to placebo.
Roodenrys
et al., 2002
R, DB, PC
n=76
healthy adults
aged 40-65yrs
300mg/d (standardised
to min 55% bacosides)
12-weeks
Significant effect on retention of
new information. Attention,
retrieval and anxiety measures
unaffected. One withdrawal due
to GIT upset in Bacopa group.
Stough
et al., 2001
R, DB, PC
n=46
healthy adults
aged 18-60yrs
12-weeks
Significantly improved speed of
information processing, learning
rate & memory consolidation &
reduced state anxiety. Adverse
reactions reported: nausea, dry
mouth & fatigue.
Nathan
et al., 2001
R, DB, PC
n=36
healthy adults
aged 18-60yrs
2-hours postadministration
No effect on various measures
of memory performance found
with acute administration of
Bacopa.
Negi et al.,
2000
R, DB, PC
n=36 children
with ADHD*
100mg/day
12-weeks
Improvements in a range of
cognitive assessments. No sideeffects reported.
Sharma
et al., 1987
Matched group
PC
n=40
healthy
children
aged 6-8yrs
350mg three times
daily
in syrup form
12-weeks
Learning, memory, perception
& reaction times improved. No
side-effects reported.
Singh &
Singh, 1980
O
n=35
adults with
anxiety
neurosis
12g/day dried Bacopa
in syrup form
4-weeks
Decreased anxiety, improved
concentration, improved
memory span. No side-effects
reported.
R= randomised, DB= double-blind, PC= placebo-controlled, O=open
* ADHD= attention deficit hyperactivity disorder
31
4.5 Conclusion
In conclusion, there are a number of in-vitro and animal studies that demonstrate
Bacopa’s potential for improving cognitive and neurological function, as well as
substantiating both antioxidant and cholinergic actions. These have been supported by
reports of memory enhancement in human clinical trials in adults and children. Most
clinical studies suggest that efficacy is evident with longer term administration
(typically 3 months) rather than shorter term administration where effects are not always
evident.
These animal and human studies validate the traditional claims of Ayurvedic medicine
in which known usage of Bacopa as a ‘brain and memory tonic’ dates back
approximately 2000 to 3000 years. Despite this, there have not as yet been any studies
that have examined Bacopa’s effect on memory specifically in older people, which is
when memory frequently begins to decline; nor in dementia, in which memory loss is a
core feature. This study, then, examined the effect of Bacopa specifically in older
people and thus contributes to filling this knowledge gap.
32
5. RESEARCH DESIGN
5.1 Introduction and overview
The aim of this study was to assess the efficacy of the herbal medicine, Bacopa
monnieri on memory performance in healthy people over the age of 55-years. It was
hypothesised that Bacopa would significantly improve memory function in older
people, and a randomised, double-blind, placebo-controlled trial was used to test this
hypothesis. This chapter describes the procedures, design and method of data collection
and its analysis.
The study commenced with an initial screening assessment. If the study criteria were
met, participants were enrolled into the study and randomised into active and placebo
groups. A neuropsychological test battery and subjective memory complaint
questionnaire were administered at a second clinical visit, to establish baseline
measurements of memory function, and participants were given tablets, instruction
sheets and medication record booklets (see Appendix I) at this visit. This was followed
by 12-weeks of supplementation with Bacopa or placebo tablets. At the end of 12weeks the neuropsychological test battery and subjective memory complaint
questionnaire were again administered and compliance and side-effects were assessed.
5.2 Location and timing
The study took place in the Natural Medicine Clinic of the School of Natural and
Complementary Medicine at Southern Cross University in Lismore, Australia between
February and July 2005.
5.3 Ethical considerations
To ensure that the wellbeing and dignity of participants was safeguarded, this study
adhered to the ethical principles and procedures as laid down by the Southern Cross
University Human Research Ethics Committee (HREC) in accordance with the National
Health and Medical Research Council Act, 1992, and the National Statement on Ethical
Conduct in Research Involving Humans. All details of the research aims, recruitment of
participants and study procedures were provided to the HREC prior to the
33
commencement of the study. Written informed consent was obtained from all
participants prior to commencement of the study (Appendix III). All participants were
given a written information sheet explaining purposes of the study and what
participation would involve as well as explaining the option to withdraw consent at any
time (Appendix III). Confidentiality was strictly maintained and only those directly
involved in the research had access to the data collected. All data from the study has
been carefully stored in a locked filing cabinet in the researcher’s office in the
university premises and will be destroyed after 5-years. Ethics approval (number ECN04-141) was obtained prior to commencement of the trial; this can be found in
Appendix II.
5.4 Recruitment of participants
Participants of both sexes, 55-years of age and above were self-selected from the
general population of the Northern Rivers region in NSW, Australia. The study was
publicised via radio, television and print media and healthy people in this age group
were invited to register their interest in participation by telephone. The trial was also
advertised electronically via staff email on the university wide intranet at Southern
Cross University.
5.4.1 Sample size
Using the R2 statistical package and nominating an effect size of 0.4 with alpha at 0.05
and a power level of Beta=0.80, a power analysis determined a prospective sample size
of 80 participants (40 in each group) for this study. Thus it was planned to enrol 100
participants in the trial to allow for a 20% dropout rate.
5.5 Procedures
One hundred and thirty-six people responded to the media release and email. These
respondents were contacted by telephone and asked brief screening questions then
enrolled for an initial clinical screening assessment.
The initial screening assessment included a comprehensive systems review, a brief
physical examination including vital signs and urinalysis, and assessment of cognitive
function and emotional state utilising the Mini-Mental State Examination (MMSE)
(Folstein et al., 1975) and the Hamilton Depression Scale (Hedlung & Vieweg, 1979).
34
All clinical data was recorded on standard Clinical Report Forms (Appendix IV). This
first clinical screening session was completed in approximately 1 hour per subject and
was carried out by a registered nurse and naturopathic clinician.
If selection criteria for the study were met (see below), the subject was then scheduled
for a baseline assessment of neuropsychological function and subjective memory
complaints (lasting approximately 1 hour). At this visit a 12-week supply of tablets was
provided and the subject was scheduled for a second, end-of-trial, assessment of
neuropsychological function and subjective memory complaints (also lasting 1 hour)
which took place twelve weeks later. All of the neuropsychological assessments at both
baseline and at end point were conducted by the same psychologist. The
neuropsychological test administration and scoring were supervised by a consultant
clinical neuropsychologist. The order and timing of the neuropsychological tests
administration was the same for each testing session, and this protocol is detailed in
Appendix V.
5.6 Selection criteria
Following the screening assessment, 103 healthy, cognitively normal men and women
over the age of 55-years were initially included in the study, with 98 of these
commencing the study drugs. Selection criteria (given below) were partly adapted from
Crook et al.’s diagnostic criteria for Age Associated Memory Impairment (1986) and
expanded to incorporate usage of either herbal medicines or recreational drugs as
exclusionary criteria.
5.6.1 Inclusion criteria
•
Age 55-years or over at commencement of trial
•
Absence of dementia as determined by a score of 24 or greater on the MiniMental State Examination (MMSE) (Folstein et al., 1975).
•
Absence of depression as determined by a score of 12 or less on the Hamilton
Depression Scale (Hedlung & Vieweg, 1979)
5.6.2 Exclusion criteria
•
Diagnosed psychiatric or neurological disorder
35
•
History of brain inflammation or infection or previous head injury resulting in
unconsciousness
•
Cerebral ischaemia as determined by a score of 4 or greater on the modified
Hachinski Ischaemia Scale (Rosen et al., 1980)
•
History of disease of any of the following bodily systems: cardiovascular, renal,
endocrine, liver, kidney, respiratory
•
Systemic disease or malignancy
•
Psychoactive medication usage including anti-depressants, anxiolytics, sedatives
or stimulants
•
Current herbal medicine usage (unless willing to discontinue for a 4-week
washout period and the duration of the trial)
•
Recreational drug use
• Alcohol abuse (defined by consumption of more than 4 standard drinks per day)
5.7 Study design
A 12-week randomised, double-blind, placebo-controlled trial was designed to provide
maximum outcomes with the resources available to undertake the study. Participants
were randomly assigned to active or placebo groups and neuropsychological tests as
well as the subjective memory complaint questionnaire were administered at baseline
and again at 12-weeks to measure the effects of Bacopa compared to placebo on
memory and cognitive function.
5.7.1 Randomisation
Following the exclusion of respondents, participants were randomly allocated into two
equal groups to receive either active treatment or placebo. Randomisation to groups was
carried out by a research academic at Southern Cross University, who had no
involvement with the study. Randomisation was generated via the following internet
randomisation website: http://www.randomization.com. This process randomised each
subject to treatment groups using the method of randomly permuted blocks. Neither the
participants nor anyone involved in conducting the research knew which group
participants were in until the data analysis stage of the research was completed.
Randomisation codes were stored electronically by the research academic who carried
out the randomisation process.
36
5.8 Compliance
At the second clinical visit (baseline assessment), participants were provided with
enough tablets to last for the twelve weeks study duration, and also ten extra tablets
were provided in case of loss or damage. Participants were also given an instruction
sheet and record booklet in which they were instructed to record their daily ingestion of
the trial medication, as well as any side-effects or symptoms experienced during the trial
(Appendix I). These booklets were collected either at the last clinical visit (end-of-trial)
or, otherwise, at the time of withdrawal from the trial. Participants were supplied with
verbal and written instructions to contact the researcher if any side-effects occurred, or
if they needed to withdraw for any reason. All tablets remaining at the end-of-trial visit
were collected and counted by the researcher. A 20% or greater discrepancy in the tablet
count was designated as constituting non-compliance (based on a similar psychopharmacological trial by LeBars et al., 1997), and would lead to exclusion from
analysis.
5.9 Materials
5.9.1 Study drugs
Bacopa monnieri was given in the form of a tablet and was derived from an alcoholic
extract of the herb (herb to extract ratio, 20:1). The extract was standardised to contain
total Bacosides 40.0 – 50.0%, along with a number of chemical constituents viz.,
Bacoside A3 (>2.7%), Bacopaside II (>3.6%), Jujubogenin isomer of Bacopa saponin C
(>4.5%), Bacopa saponin C (>3.0%), Bacopaside I (>4.5%), Apigenin (0.1 – 0.5%) and
Luteolin (0.1 – 0.8%).
The extract was supplied by Natural Remedies Pvt. Ltd. in Bangalore, India, following a
proprietary manufacturing method. The name of this standardised extract is
Bacomind™, code number NRBME40, tableted by Tabco Pty Ltd and supplied by
Herbs of Gold Pty Ltd, Australia. Each 300mg of Bacomind™ in a tablet contains
6000mg equivalent of the dried herb. The dosage instructed was 300mg of Bacomind™
in one tablet daily, after a meal. Film-coated placebo tablets were identical in size,
colour and shape to that of the Bacopa tablets. Specification sheets for Bacomind™ and
placebo tablets can be found in Appendix VI. The dosage of Bacopa was based on the
37
manufacturers’ recommendation and was the same as that used in previous clinical trials
by Stough et al. (2001) and Roodenrys et al. (2002).
5.10 Instruments
5.10.1 Screening instruments
The following instruments were utilised in the pre-trial screening session, to measure
selection criteria.
5.10.1.1 The Mini Mental State Examination (MMSE)
This is a widely used test to screen for cognitive dysfunction. This test was developed
by Folstein et al. in 1975 to determine degrees of cognitive impairment. There are 12
items with a total possible score of 30, with higher scores reflecting better cognitive
function. Scores above 21 reflect normal function and mild impairment, scores ranging
from 10-20 indicate moderate impairment, and severe impairment is indicated by scores
of 9 or less. A copy of the MMSE form used can be found in the Clinical Report Form
in Appendix IV.
5.10.1.2 The Hamilton Rating Scale for Depression (HAM-D)
A 21-item version of the Hamilton Rating Scale for Depression (adapted from Hedlung
& Vieweg, 1979 by GlaxoWellcome) was utilised from the following website:
http://healthnet.umassmed.edu/mhealth/HAMD.pdf. A copy of this form can be found
in the Clinical Report Form in Appendix IV. The possible scores on this scale range
from 0-66, with higher scores reflecting worse depression. Scores above 13 indicate
depression, and below 13 imply absence of depression.
5.10.1.3 Modified Hachinski Ischemic Score (HIS)
The Hachinski Ischaemic Score was developed in 1975 to enable clinicians to
distinguish between multi-infarct aetiology and degenerative aetiology in patients
presenting with dementia (Hachinski et al., 1975). The modified version of the scale,
utilised in the current study was introduced by Rosen et al. in 1980. This scale rates
symptoms of ischaemic cerebrovascular events. There are eight items, with a total
possible score of 12-points. A score above 3 indicates multi-infarct dementia. A copy of
the scale can be found in the Clinical Report Form (Appendix IV). In the current study
38
the Modified Hachinski Ischaemic scale was used to screen for cognitive deficits related
to ischaemia and stroke.
5.10.2 Primary outcome measures
The following instruments were used to give both objective and subjective
measurements of memory at baseline and end-of-trial clinical sessions.
5.10.2.1 Rey Auditory Verbal Learning Test (AVLT)
The Rey Auditory Verbal Learning Test (AVLT) (Rey, 1964), is a word list learning
test that is a validated and widely used test for assessing memory in both clinical
practice and research (Lezak et al., 2004:421). A copy of the AVLT can be found in
Appendix VII. Its usage has been extensively reported in the literature (Schmidt, 1996).
Numerous publications have established norms for the AVLT (for example Ivnik et al.,
1990), and Australian norms for the test have also been established (Forrester &Geffen,
1991; Geffen et al., 1990; Rickert & Senior, 1998). The AVLT assesses various aspects
of memory, as outlined below.
In the AVLT the same 15-word list (List A) is read to the participant for five repetitions
(AVLT a1-5). After each repetition, the subject recalls as many words as possible from
the list. During a sixth trial (AVLT b), words are presented from a different fifteen word
list, an interference list, (List B), which must be recalled by the subject, followed
immediately by a sixth recall of the original list, List A (AVLT a6). A seventh recall of
List A (AVLT a7) occurs after a 20-minute interval. The last part of the test consists of
a recognition task (AVLT recognition) wherein a list of fifty words is read to the subject
who must identify the 15-words from List A embedded amongst 35 other words
(including semantically and phonetically similar words as well as the 15-words from
List B). Specific instructions for the administration of the AVLT are given in Lezak et
al. (2004: 421-426) and these were adhered to in the trial.
Alternate word lists for the AVLT were used at the end-of-trial assessment to avoid
learning effects. These lists were developed by Jones-Gotman, Szilkas & Majdan (cited
in Lezak et al., 2004: 423). The alternate AVLT word lists used at the end-of-trial
assessment can be viewed in Appendix VIII.
39
From the raw scores obtained on the AVLT a number of measures of memory function
were obtained as follows (Lezak et al., 2004:422-426):
•
AVLT trial a1: immediate recall
•
AVLT trial a6: recall post intrusion
•
AVLT trial a7: delayed recall (assesses long term retention)
•
AVLT trials a1-a5, summed scores: total learning
•
AVLT trial a5 minus trial a6: retroactive interference
•
AVLT trial a1 minus trial b: proactive interference
•
AVLT recognition hit rate (correctly identified list A words)
•
AVLT recognition false positives (words incorrectly identified as list A words)
•
AVLT true recognition rate (recognition hit rate minus false positives)
•
AVLT trial a6 minus trial a7: forgetting rate
5.10.2.2 Rey-Osterrieth Complex Figure Test (CFT)
The Rey-Osterrieth Complex Figure Test (Rey, 1941; Osterrieth, 1944; Corwin &
Bylsma, 1993) is used to assess visuospatial ability and visual memory (Spreen &
Strauss, 1991:157). A complicated geometrical figure (the Rey-Osterrieth figure)
(Appendix IX), is presented to the subject, who is asked to copy it initially and then
reproduce it from memory twice- firstly 3-minutes, and then 30-minutes, later. Scoring
involves giving marks for both placement and accuracy of 18 different components of
the drawing. Total possible score equals 36 for each trial. A copy of the CFT marking
sheet is in Appendix X.
5.10.2.3 Trail Making Test (TMT)
The Trail Making Test (Reitan, 1958), is a test which measures scanning and visuomotor tracking abilities, and involves cognitive processing (incorporating memory) as
well as psychomotor speed (Lezak et al., 2004: 371). There are two separate parts of the
test- part A and part B (Appendix XI). In part A (Trails A), the subject must draw a line
connecting circles containing consecutive numbers (from number 1 to number 25). In
part B (Trails B), the subject again draws a line between circles, though now alternating
between consecutive numbers and letters, i.e. from 1 to A to 2 to B and so on up until
the number 13 and the letter L. The subject performs the task as fast as he/she can,
40
while their pen does not lose contact with the paper. The scores obtained are the times
taken (in seconds) to complete the two tasks.
5.10.2.4 Memory Complaint Questionnaire (MAC-Q)
The Memory Complaint Questionnaire (Crook et al., 1992) was designed as a brief
screening tool to measure experiential memory deterioration with aging, thereby
quantifying subjective memory complaints. Participants answer six questions comparing
current everyday memory to that of earlier life. The total score is the sum of the six
questions, scored on a 5-point Likert scale, with options ranging from ‘much better
now’ to ‘much worse now’. The possible score range is 7-35, with scores over 25
indicating subjective memory impairment. This Memory Complaint Questionnaire can
be found in Appendix XII.
5.11 Statistical analysis
All data in this study were analysed using the computer software package- Statistical
Package for the Social Sciences (SPSS version 11.5 for Windows). For the primary
efficacy analysis, neuropsychological test scores and subjective memory complaints
scores were analysed using a repeated measures analysis of variance (ANOVA)
employing group (Bacopa and placebo) and time (baseline and week 12) as between and
within subject factors.
To test the successfulness of randomisation, potential difference between groups
(Bacopa and placebo) on all variables at baseline was analysed using independent
samples t-test for continuous variables and chi-square test for categorical variables.
To determine whether gender, age, education and marital status affected memory in
both groups, baseline test scores were analysed by independent t-tests for age and
education, and by Pearson’s product-moment correlations for gender and marital status.
Side-effects as reported either verbally or in the participants’ record booklets, were
analysed using an independent samples t-test for significant differences between active
and placebo groups.
41
In summary, this chapter has described the research carried out, including participants
and procedures, selection criteria, study design, study drugs and the instruments used to
measure outcomes. Finally, the statistical analysis techniques used in the study were
described. Chapter 6 will report on the results obtained from this analysis.
42
6. RESULTS
6.1 Introduction
Following on from the previous chapter which gave an in-depth description of the
design of the research, this chapter will report the research results. Firstly, analysis of
the flow of participants through the clinical trial will be presented. Next, the clinical
characteristics and baseline measurements will be reported with analysis of baseline
group differences and the effects of gender, marital status, age and education on
performance. The analysis of study compliance, side-effects and withdrawals will be
elucidated and, lastly, the results obtained from the primary outcomes analysis will be
presented.
6.2 Participants
136 people volunteered for participation in the trial. Of these, 103 met the study
selection criteria and 98 commenced the trial. Of those commencing, 52 (53.1%) were
females and 46 (46.9%) were males. The average age of participants was 65-years
(range 55-86, SD 7.53) and they had an average of 13-years of education (range 5-22,
SD 4.01). 26 participants were single and 72 were married or defacto.
81 participants completed the study and 17 withdrew. Of the completers, there were 42
(51.9%) females and 39 (48.1%) males, with an average age of 65.4-years (range 55-86,
SD 7.67) and an average of 13-years of education (range 5-22, SD 4.08). 18
participants were single and 63 were married or defacto.
6.2.1 Exclusions
Of the 136 applicants, a total of 33 people were initially excluded from the trial for the
following reasons (for some respondents more than one reason applied):
•
Psychiatric illness: depression (n=1)
•
Neurological disease: Parkinson’s disease (n=2), essential tremor (n=1), recent
loss of consciousness (n=1), chronic back pain (n=1)
•
Cardiovascular disease: ischaemic heart disease (n=4), atrial fibrillation (n=2),
valvular heart disease (n=1), stroke (n=1)
43
•
Other systemic illness: thyroid disease (n=1), systemic lupus erythematosus
(SLE) (n=1)
•
Medication usage: antidepressants (n=10), anxiolytic (n=1), opiate use (n=1),
sleep medication (n=1)
•
Herbal medicine usage (n=2)
•
Mini Mental Status Examination score under 24 point cut-off (n=2)
•
Under 55 years of age (n=3)
•
Exclusion of partner (n=1)
•
Unwilling to be on placebo (n=1)
•
Work commitments that would effect compliance (n=1)
6.2.2 Randomisation
Following exclusion, participants were randomised into groups using the protocol
previously described in section 5.7.1. To assess whether equal distribution into groups
was achieved by randomisation, the means were calculated and group differences
analysed by independent t-test for the following continuous variables recorded at
baseline: age, education, MMSE scores, Hamilton Depression Scale scores,
neuropsychological test scores and the memory complaint questionnaire scores. The
categorical variables of gender and marital status were analysed for group differences
using the chi-squared test.
The clinical characteristics and baseline neuropsychological test scores of those who
commenced the trial are summarised in Table 6.1. As indicated in this table, there were
significant differences found between the active and placebo groups mean scores on the
Complex Figure Test (CFT) in both the 3-minute and the 30-minute delayed recall
tasks. The Bacopa group performed better than the placebo group on these tasks at
baseline. However, no interactions between the active and placebo groups on gender,
age group and education level were found. The mean scores on the CFT tasks were
fairly low and the means varied between groups by only 4 marks out of a total possible
score of 36 marks. Following consultation with the university’s professional statistician
it was considered that this is not a large difference and since the scores were normally
distributed it is likely that the differences found on these tasks was due to chance. On all
other neuropsychological measures and demographic characteristics, there were no
44
significant differences found between groups. With these findings and minor limitations
it seems randomisation was generally successful.
Table 6.1: Dependent variables at baseline: clinical characteristics and test scores at point
of randomisation (n=98), with analysis of group differences.
Total Sample
Number of Subjects
Bacopa Group
Placebo Group
p
98
49
49
-
52(53%)/46(47%)
24(49%)/25(51%)
28(57%)/21(43%)
0.54
65+/-7.53
65.41+/-6.87
65.39+/-8.20
0.989
55-86
55-77
55-86
-
13+/-4.01
13.37+/-3.97
12.82+/-4.07
0.5
5-22
5-20
6-22
-
72(73%)/26(27%)
35(71%)/14(29%)
37(75%)/12(25%)
0.81
28.18+/-1.56
28.05+/-1.63
28.30+/-1.50
0.423
Hamilton Depression Scale
3.28+/-2.89
3.07+/-2.73
3.48+/-3.05
0.488
AVLT a1
5.91+/- 1.62
5.94+/-1.63
5.88+/-1.62
0.853
AVLT a2
7.63+/-2.25
7.8+/-2.48
7.47+/-2.02
0.477
AVLT a3
8.68+/-2.30
8.73+/-2.29
8.63+/-2.32
0.828
AVLT a4
9.36+/-2.08
9.33+/-2.13
9.39+/-2.06
0.885
AVLT a5
10.17+/-2.48
10.37+/-2.44
9.98+/-2.53
0.443
AVLT b (interference list)
4.28+/-1.90
4.33+/-2.01
4.22+/-1.81
0.793
AVLT a6
7.85+/-2.82
8+/-2.83
7.69+/-2.83
0.594
AVLT a7 (20minute recall)
7.58+/-2.79
7.86+/-2.52
7.31+/-3.05
0.332
AVLT recognition hit rate
12.45+/-2.39
12.71+/-2.09
12.18+/-2.65
0.274
AVLT false positive rate
3.64+/-3.20
3.43+/-3.27
3.86+/-3.15
0.511
Gender (female/male)
Age (years)
-range
Education (years)
-range
Marital Status (partner/single)
MMSE
AVLT true recognition rate
8.81+/-3.84
9.29+/-3.71
8.33+/-3.94
0.218
AVLT total learning (Σ1-5)
41.67+/-8.91
42.16+/-9.42
41.18+/-8.44
0.589
AVLT retroactive interference
2.33+/-1.97
2.37+/-1.99
2.29+/-1.96
0.839
AVLT proactive interference
1.63+/-1.98
1.61+/-1.95
1.65+/-2.03
0.92
.27+/-1.62
0.14+/-1.70
0.39+/-1.53
0.458
CFT copy
34.24+/-2.85
34.45+/-2.21
34.03+/-3.38
0.471
CFT 3min
16.45+/-6.41
18.24+/-6.43
14.65+/-5.93
0.005**
CFT 30min
16.58+/-6.37
18.26+/-5.92
14.89+/-6.42
0.008**
AVLT forgetting rate
MAC-Q
26.07+/-4.56
25.84+/-3.78
26.31+/-5.25
0.613
Trail Making Test A
36.05+/-9.48
34.27+/-7.95
37.84+/-10.59
0.062
Trail Making Test B
87.07+/-33.54
88.02+/-31.61
86.12+/-35.66
0.781
Results are mean+/-SD unless otherwise specified. Chi-square test for gender and marital status.
Independent t-test for age, education and neuropsychological tasks. p = two-tailed significance, for
differences between groups. MMSE = Mini-Mental State Examination, AVLT = Rey Auditory Verbal
Learning Test, CFT = Rey-Osterrieth Complex Figure Test, MAC-Q = Memory Complaint
Questionnaire.
**p<.01
45
6.2.3 Effects of gender, marital status, age and education on
baseline measures
The effects of the independent variables on baseline neuropsychological and subjective
memory complaints scores were analysed using independent samples t- test for the
effects of gender and marital status and using Pearson’s product moment correlation for
the effects of age and education. Results are outlined below.
6.2.3.1 Gender
An independent samples t-test was applied to compare all the baseline memory test
scores for males and females. Females performed significantly better than males in
some of the AVLT tasks as shown in Table 6.2 below.
Table 6.2: Significant effects of gender on task performance at baseline (n=98)
TASK
t
Sig.
AVLT 2
2.012
.047
AVLT 3
3.123
.002
AVLT 4
2.323
.022
AVLT 5
3.429
.001
AVLT 7
2.349
.003
AVLT total 1-5
3.000
.003
t=independent samples t-test value for differences between
females and males
Sig. = two–tailed significance
6.2.3.2 Marital status
Using an independent samples t-test, there were no significant differences found for
performance of married/defacto participants compared to single/widowed participants
on baseline test scores.
6.2.3.3 Age
The relationship between age and all the baseline neuropsychological test scores was
investigated using Pearson’s product-moment correlation coefficient. Advancing age led
to reductions in performance as evidenced by the significant correlations between age
and various dependent variables as shown in Table 6.3 below.
46
Table 6.3: Significant effects of age on task performance at baseline (n=98)
TASK
r
Sig.
Strength & direction
of correlation
AVLT 2
-.228
.024
small negative
AVLT 3
-.234
.021
small negative
AVLT 4
-.201
.047
small negative
AVLT 5
-.239
.018
small negative
AVLT b
-.394
000
medium negative
AVLT 6
-.210
.038
small negative
AVLT 7
-.223
.027
small negative
AVLT total 1-5
-.237
.019
small negative
AVLT proactive*
.312
.002
medium positive
CFT a (3min)
-.300
.003
medium negative
CFT b (30min)
-.247
.014
small negative
TMT A*
.279
.005
small positive
TMT B*
.392
.000
medium positive
r= Pearson’s product-moment correlation coefficient; Sig. = two–tailed significance
*on these tasks higher scores = worse performance
6.2.3.4 Education
The relationship between education and all baseline test scores was investigated using
Pearson’s product-moment correlation coefficient. Higher levels of education
significantly improved test scores as evidenced by significant correlations between
education and the following dependent variables as shown in Table 6.4 below.
47
Table 6.4: Correlation of length of education and task performance at baseline (n=98)
TASK
r
Sig.
Strength & direction
of correlation
AVLT 1
.223
.028
small positive
AVLT 2
.307
.002
medium positive
AVLT 3
.284
.005
small positive
AVLT 5
.265
.008
small positive
AVLT b
.238
.019
small positive
AVLT 6
.331
.001
medium positive
AVLT 7
.241
.017
small positive
AVLT total 1-5
.295
.003
small positive
AVLT falspos*
-.243
.016
small negative
AVLT truerec
.239
.018
small positive
CFT copy
.325
.001
medium positive
CFT 3min
.411
.000
medium positive
CFT 30min
.383
.000
medium positive
TMT B*
-.342
.001
medium negative
*on these tasks higher scores = worse performance
r= Pearson’s product-moment correlation coefficient
Sig. = two–tailed significance
6.2.4 Group distribution by age and gender categories.
The age of participants was categorised into three groups: 55-65years, 66-75years and
76-86years. Education was categorised into three levels: primary (5-7years), secondary
(8-13years) and tertiary (14-22years). The distribution of age groups and educational
levels at the point of randomisation are given in Figures 6.1 and 6.2.
48
30
Number of cases
20
Group
10
Bacopa
(n=49)
Placebo
0
(n=49)
55-65
66-75
76-86
Age group
Figure 6.1: Distribution of age groups at point of randomisation (n=98)
30
25
20
Number of cases
15
Group
10
Bacopa
(n=49)
5
Placebo
0
(n=49)
primary
secondary
tertiary
Educational level attained
Figure 6.2: Distribution of educational levels at point of randomisation (n=98)
49
6.2.5 Compliance
All participants who completed the trial complied with medication use. This was
assessed by a count of tablets remaining in containers returned at the end of the trial. A
discrepancy from the study regimen of 20% or greater constituted as non-compliance.
Additionally, compliance was monitored by checking the completed medication record
booklet handed over by participants (see Appendix I) and also by verbal questioning at
the end point clinic session. In a small number of cases (n=11) participants forgot to
return their tablets, in these cases only the written record and verbal questioning were
used to assess medication compliance.
6.2.6 Study withdrawals
Of the 98 participants who commenced the study, 81 participants completed the trial. A
total of 17 (10 females and 7 males) withdrew after the baseline testing session, 13 from
the Bacopa group and 4 from the placebo group. The reasons for withdrawal from the
trial for the Bacopa and placebo groups as shown in Table 6.5 includes side-effects n= 9
for Bacopa group and n= 2 for placebo group.
Table 6.5: Reasons for withdrawal from trial
Reason for withdrawal
Total
Bacopa
Placebo
Group
Group
Side-effects
11
9
2
Hospitalisation for elective surgery
1
0
1
Concurrent illness
2
1
1
Accidental injury
1
1
0
Lost to follow-up
2
2
0
A flow chart which illustrates the progression of participants through the phases of the
clinical trial is presented in Figure 6.3 (below). This flow chart is based on a model
designed by Moher et al. (2001).
50
Assessed for eligibility
(n=136)
Excluded (n=33)
-selection criteria not met (n=30)
-declined consent (n=1)
-other reasons (n=2)
Randomised
(n=103)
Allocated to receive Bacopa (n=51)
Allocated to receive Placebo (n=52)
Received intervention (n=49)
Received intervention (n=49)
Did not receive intervention:
Did not receive intervention:
-work commitments (n=1)
-work commitments (n=1)
-death in family (n=1)
-travel (n=1)
-lost to follow up (n=1)
Followed up at 12-week visit
Followed up at 12-week visit
(n=36)
(n=45)
Withdrawn after baseline (n=13):
Withdrawn after baseline (n=4):
-side effects (n=9)
-side effects (n=2)
-lost to follow up (n=2)
-elective surgery (n=1)
-concurrent illness (n=1)
-concurrent illness (n=1)
-accident (n=1)
Analysed (n=36)
Analysed (n=45)
Figure 6.3: Flow-chart depicting participant progression through phases of the
clinical trial.
51
6.2.7 Side-effects
Participants recorded any possible side-effects in the record booklet (Appendix I), and
were also instructed to inform the researcher immediately in the event of any suspected
reaction occurring. There were a total of 52 possible side-effects reported during the
trial, 41 of these occurred in the Bacopa group, and 11 occurred in the placebo group
(note that more than one event could be reported by participants.) Table 6.6 documents
the total number of side-effects reported.
Table 6.6: Total side-effects reported during study
Symptoms reported*
Bacopa
Placebo
Group
Group
Increased stool frequency
15
1
GIT cramps
8
0
Nausea
9
1
Reflux
0
2
Flatulence
1
0
Bloating
1
2
Decreased appetite
1
0
Constipation
0
1
Headache
1
1
Hypertension
0
1
Insomnia
1
0
Vivid dreams
2
0
Increased sense of wellbeing
2
2
*Participants could report more than one symptom; includes study withdrawals
51% (25/49) of participants in the Bacopa group reported at least one side-effect
compared with 18% (9/49) in the placebo group. The severity of symptoms reported
was mild to moderate and transient, with only one serious event reported- that of
hypertension (in the placebo group). However, symptoms were severe enough to
warrant withdrawal from the study in 18% (9/49) of the Bacopa group and 4% (2/49) of
the placebo group. All side-effect related withdrawals in the Bacopa group were due to
GIT symptoms.
52
Overall, GIT symptoms occurred predominantly in the Bacopa group, with 45% (22/49)
of subjects reporting at least one GIT symptom as compared to the placebo group, in
which 10% (5/49) of subjects reported at least one GIT symptom. The predominant GIT
symptoms reported were increased stool frequency, abdominal cramps and nausea.
These were transient and ceased on discontinuation of tablets. Other bodily systems in
which side-effects were reported were the nervous system (headache, insomnia, vivid
dreams, enhanced sense of wellbeing), and the cardiovascular system (hypertension).
Due to unequal drop-out rates, only 73% (36/49) of the Bacopa group completed the
study, compared to 92% (45/49) of the placebo group.
An independent samples t-test was applied to test for significant differences in side
effects experienced between treatment groups. The following side-effects occurred
significantly more often in the Bacopa group compared to placebo (at 95% confidence
interval): increased stool frequency (t=4.106, p=.000), nausea (t=2.744, p=.007),
abdominal cramps (t=3.060, p=.003), and total GIT side-effects (t=4.128, p=.000).
53
6.3 Primary outcome measurements
The means and standard deviations for all dependent variables by group and testing
session are presented in Table 6.7 below
Table 6.7: Mean (and SD) for all tasks by group and testing session
Bacopa Group
Task
Placebo Group
Pre-test
Post-test
Pre-test
Post-test
(n=36)
(n=36)
(n=45)
(n=45)
AVLTa1
5.75
(1.70)
5.64
(1.62)
5.72
(1.52)
5.22
(1.56)
AVLTa2
7.47
(2.39)
7.92
(1.98)
7.51
(2.05)
7.40
(2.18)
AVLTa3
8.64
(2.22)
9.28
(2.17)
8.69
(2.29)
8.49
(2.38)
AVLTa4
9.22
(2.11)
10.69
(1.90)
9.33
(2.07)
8.96
(2.18)
AVLTa5
10.33
(2.51)
11.06
(2.18)
9.96
(2.50)
9.38
(2.36)
AVLTb
4.33
(1.99)
4.64
(1.78)
4.29
(1.83)
4.76
(1.58)
AVLTa6
7.94
(3.07)
9.83
(2.04)
7.73
(2.91)
7.16
(2.04)
AVLTa7
7.94
(2.75)
9.58
(2.17)
7.36
(3.10)
6.84
(2.66)
AVLTrec
12.61
(2.22)
13.86
(1.15)
12.38
(2.52)
13.13
(2.12)
AVLTfalspos
3.47
(3.53)
1.92
(2.34)
4.02
(3.18)
3.49
(3.61)
AVLTtrue rec
9.14
(3.93)
11.94
(2.62)
8.36
(3.91)
9.64
(4.11)
AVLTtotal1-5
41.42
(9.25)
44.31
(8.52)
41.20
(8.44)
39.42
(9.22)
AVLTretroactive
2.39
(2.10)
1.22
(1.57)
2.22
(2.01)
2.22
(1.61)
AVLTproactive
1.42
(1.90)
1.00
(1.93)
1.60
(2.07)
0.47
(1.53)
AVLTforget
0.00
(1.79)
0.25
(1.27)
0.38
(1.60)
0.31
(1.55)
CFTcopy
34.43
(2.33)
32.80
(4.99)
33.90
(3.50)
33.54
(2.77)
CFTa
18.08
(5.84)
19.57
(5.85)
14.14
(5.73)
17.77
(6.93)
CFTb
18.40
(5.30)
20.46
(6.10)
14.49
(6.41)
18.11
(6.32)
MAC-Q
25.89
(3.52)
22.39
(5.35)
26.38
(5.37)
24.69
(4.57)
Trail Making A
33.56
(7.58)
30.72
(8.98)
37.87
(10.74)
35.58
(14.70)
Trail Making B
89.89
(32.25)
71.81
(27.47)
86.29
(36.92)
75.47
(22.32)
AVLT = Rey Auditory Verbal Learning Test, AVLTa1-a7 = repetitions of word list A (possible range 015), AVLT b = interference word list B (possible range 0-15), AVLT rec = recognition list hit rate
(possible range 0-15) , AVLT falspos = recognition list false positives (possible range 0-35), AVLT true
rec = true recognition (recognition list hit rate minus false positives, possible range -35 to +15) , AVLT
total 1-5 = total learning score (sum of trials a1 to a5, range 0-75), AVLT retroactive = retroactive
interference score (trial a5 minus trial a6, possible range -15 to +15, lower scores = better performance, ),
AVLT proactive = proactive interference score (trial a1 minus trial b, possible range -15 to +15, lower
scores = better performance), AVLT forget = forgetting rate (trial a6 minus trial a7, possible range -15 to
+15, lower scores = better performance); CFT = Rey-Osterrieth Complex Figure Test (possible range 036 on all tasks), CFTcopy=copy task, CFTa=3-minute recall task, CFTb=30-minute recall task; MAC-Q
= Memory Complaint Questionnaire (possible range 7-35, lower scores = better performance); Trail
Making Test A & B- scores=time taken to complete task (in seconds).
54
Initially, the normality of the distribution of scores for each of the continuous variables
was tested and it was found that the assumptions of normality were met. A General
Linear Model (GLM) was run to test for significant differences between the Bacopa and
placebo groups on all dependent variables (memory complaint questionnaire and
neuropsychological test scores) from baseline to end-of-trial. A Repeated Measures
Analysis of Variance (ANOVA) was used with time (baseline and end point scores) as
the within subjects factor, and treatment group (Bacopa and placebo) as the between
subjects factor. Type 1 sum of squares was employed. At the 0.05 probability level,
Bacopa significantly improved memory function as measured by performance on the
following AVLT tasks: trial a4, trial a5, trial a6 (post distraction trial), trial a7 (delayed
recall trial), total learning (Σ trials a1-a5), and retroactive interference index. Table 6.8
summarises these results. Figures 6.4 to 6.9 inclusive illustrate the treatment effects of
Bacopa compared to placebo for each of these outcome measures.
Improved performance was also noted on the CFT and the TMT - however on these two
tests there were no significant effects for Bacopa compared to placebo- both groups
improved. Likewise, on the subjective memory complaint questionnaire, both placebo
and Bacopa groups had improved scores. For a summary of the Repeated Measures
Analyses results for all tasks refer to Appendix XIII.
Table 6.8: Significant group differences on primary outcome measures: results of repeated
measures analysis of variance
Task
F
df
Error Sig.
df
AVLT trial a4
13.204
1
79 .000
AVLT trial a5
6.097
1
79 .016
AVLT trial a6 (recall post-intrusion)
18.830
1
79 .000
AVLT trial a7 (delayed recall)
12.021
1
79 .001
AVLT trial Total Learning (Σ trials 1-5)
6.761
1
79 .011
AVLT retroactive interference index
4.020
1
79 .048
F= Fisher value for significance of group contrasts. df=degrees of freedom for the two treatment groups,
error df=degrees of freedom for error. Sig.=one-tailed significance. AVLT = Rey Auditory Verbal
Learning Test, AVLTa4-a7 = repetitions of word list A recall task (possible range 0-15), AVLT Total
Learning = total learning score (sum of trials a1 to a5, possible range 0-75), AVLT retroactive =
retroactive interference score (trial a5 minus trial a6, possible range -15 to +15, lower scores = better
performance).
55
Estimated Marginal Means of AVLT trial a4
11.0
Estimated Marginal Means
10.5
10.0
Group
9.5
Bacopa
(n=36)
9.0
Placebo
(n=45)
8.5
Baseline
End-of-trial
TIME
Figure 6.4: Profile plot showing the effects of Bacopa versus placebo for AVLT trial a4
11.5
11.0
10.5
Group
10.0
Bacopa
(n=36)
9.5
Placebo
(n=45)
9.0
Baseline
End-of-trial
TIME
56
(post distraction trial)
10.0
9.5
9.0
8.5
Group
8.0
Bacopa
7.5
(n=36)
7.0
Placebo
(n=45)
6.5
Baseline
End-of-trial
TIME
(delayed recall trial)
10.0
9.5
9.0
8.5
Group
8.0
Bacopa
7.5
(n=36)
7.0
Placebo
(n=45)
6.5
Baseline
End-of-trial
TIME
trial a7
57
Estimated Marginal Means of Total Learning
(sum of scores of AVLT trials 1-5)
45
44
43
Group
42
Bacopa
41
(n=36)
40
Placebo
(n=45)
39
Baseline
End-of-trial
TIME
Figure 6.8: Profile plot showing the effects of Bacopa versus placebo for AVLT total
learning index (sum of trials a1-a5)
Estimated Marginal Means, low scores=best performance
of retroactive interference index
2.6
2.4
2.2
2.0
Group
1.8
1.6
Bacopa
1.4
(n=36)
1.2
Placebo
1.0
(n=45)
Baseline
End-of-trial
TIME
retroactive interference index (lower scores = better performance)
58
To conclude, this chapter has outlined the results obtained from the statistical analysis
of the study data. The flow of participants through the trial was documented, the effects
of gender, marital status, education and age on baseline scores were delineated and the
distribution of age and education levels was presented. Study compliance, withdrawals
and side-effects were documented and, finally, the results of the primary outcome
measurements analyses were reported. The next chapter will examine these results in
relation to the previous literature and explore the implications of the findings obtained.
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7. DISCUSSION
7.1 Introduction
This study was designed to test firstly, whether previously reported findings of the
beneficial effects of Bacopa monnieri on human memory (Stough et al., 2001;
Roodenrys et al., 2002), were replicable in the elderly population, and secondly,
whether Bacopa would produce side-effects. Previously validated neuropsychological
tests were used to objectively measure verbal and visual memory, and a memory
complaint questionnaire was used to obtain a subjective measurement of memory
function.
Analysis of the data revealed a significant effect of Bacopa on memory performance in
Australians over the age of 55 years. This effect was objectively measured by
performance outcomes on the test of auditory verbal learning- the AVLT. Performances
on tests measuring visuospatial memory- the CFT and the TMT- improved across the
total sample population, however the differences found between active and placebo
groups on these tests did not reach significance. Likewise, the whole study population
demonstrated subjective memory improvement as measured by the Memory Complaint
Questionnaire (MAC-Q), but the Bacopa group not significantly more so than placebo.
Additionally, Bacopa use was significantly associated with gastrointestinal (GIT) sideeffects of mild to moderate degrees of intensity in almost half of the participants who
were on it.
7.2 Effects of age, gender and education on baseline
measurements
As noted in the results section significant correlations were found between baseline
neuropsychological test scores and gender, age and education level. Higher education
levels improved performance on all three tests, whereas advancing age decreased
performance on all three tests and women performed better than men on AVLT tasks
(but not CFT or TMT). These findings concur with the bulk of research literature.
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For example, the AVLT scores significantly worsen with age as demonstrated in
numerous correlational and normative studies (Schmidt, 1996:31). Ivnik et al. (1990)
comment that effects of ageing on AVLT scores is accentuated in older rather than
younger groups. Age effects on the CFT recall tasks also have been consistently
documented (Lezak et al., 2004:459), and poorer scores with ageing have also been
demonstrated on the TMT (ibid: 373).
Education has the opposite effect on scores: the more educated, the better the
performance on the AVLT (Schmidt, 1996:32) as well as the CFT (Lezak et al.,
2004:459) and the TMT in which education effects are especially evident in Part B
rather than Part A (ibid: 373). For example, Geffen et al., who published Australian
norms for the AVLT which included older age groups, showed enhanced performance
on trials 2-5 with higher education levels (Geffen et al., 1990). Other Australian norms
for the AVLT published by Rickert and Senior also reported significant effects for age
and education level (1998). However, the effect of education on AVLT performance is
generally weaker and less consistent than that of age (Schmidt, 1996:32).
A gender effect has been found but has not been consistently evident for the AVLT
(Schmidt, 1996:32), though where it has been reported the same pattern emerges as
noted in the current study, i.e. women outperform men. For example, in Geffen et al.’s
Australian study, women consistently performed significantly better than men on the
AVLT (1990). Conversely, gender differences on the CFT tend to favour males, though
inconsistently (Lezak et al., 2004:459), and men have been shown to perform better on
the TMT part B, particularly in older age groups (Lezak et al., 2004:373). Gender
effects on the CFT and TMT were not noted in the current trial.
7.3 Primary outcome measures
7.3.1 The Rey Auditory Verbal Learning Test (AVLT)
Compared to placebo, Bacopa significantly improved performance on the AVLT in the
following tasks: trials a4 (p=.000), a5 (p=.016), a6 (p=.000), a7 (p=.001), sum of trials 15 (i.e. the total learning score) (p=.011), and retroactive interference (p=.048).
Performance on these trials demonstrated that Bacopa had a significant effect on
memory acquisition and retention. Participants on Bacopa showed a significant
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improvement in their capacity for verbal learning with repetition, unlike those on
placebo whose performance either plateaued or marginally decreased on these
measures. Improvement in memory acquisition was demonstrated by an increasing
amount of words recalled over the 5 learning trials that were retained at the delayed
recall trial, a7 (Lezak et al., 2004:428). Performance on the delayed recall trial also
demonstrates improved memory retention. Furthermore, retention of the learned
material was less affected by the introduction of an interference word list (B), as
evidenced by significantly improved retroactive interference scores in the Bacopa
group.
Attention span is considered to be a significant element contributing to performance on
the first AVLT word list recall trial al., compared to the subsequent learning trials
(Macartney-Filgate and Vriezen, 1988). In the current study, the improvement in
memory acquisition contrasts with attention span performance, as measured by the first
trial, a1, where no effect for Bacopa was found. Therefore, these findings imply that
Bacopa improves memory acquisition and retention as opposed to immediate attention
span.
The finding of improved memory retention concurs with the findings of Roodenrys et
al. (2002) who also found a significant effect of Bacopa on retention of new
information. Unlike Roodenrys et al., who suggest that Bacopa improves retention by
decreasing forgetting rate rather than by improving learning rate, however, the current
study demonstrated an improved learning rate and no effect on forgetting rate. It is
notable that Roodenrys et al.’s measurement of retention was based on performance on
a word pair test which involved three learning trials and a fourth delayed recall trial of
six unrelated word pairs. It was only in the delayed recall trial that an effect was found.
On the test used in the current study, no significant enhancement of learning occurred in
the first three learning trials either, it was not until the fourth, fifth, sixth and seventh
trials that significant effects were observed. Thus, it may be that insufficient learning
trials were applied in the Roodenrys et al. study to demonstrate that learning had
occurred, rather than that a learning effect did not occur as they had surmised.
The current study also concurs with the findings of Stough and colleagues (2001), who
reported improvements on various measures from the AVLT, in that Bacopa
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significantly improved learning rate (acquisition) and memory consolidation (assessed
by decreased proactive interference and decreased forgetting rate). Memory
consolidation refers to the complex molecular processes by which information is moved
from short term memory into long term memory, i.e. how memories become ‘solid’
(Carlson, 2002:383). The current study concurs with Stough et al.’s finding of improved
learning and consolidation, however differs in that improvement in memory
consolidation was not associated with improvements in proactive interference or
forgetting rate for which no effects were found. Rather, the current study suggests that
the observed enhancement of memory consolidation may be related to reduced
retroactive interference (p=0.048), as explained below.
Interference effects on memory are categorised into two types- proactive and retroactive
(Lezak et al., 2004:428). Proactive interference occurs when earlier learning disrupts
later learning, for example- learning words from an original word list interferes with
learning words from a second list. Retroactive interference occurs when later learning
disrupts earlier learning, for example- learning words from a second list interferes with
recall from an original word list. As noted above, the capacity to withstand retroactive
interference was significantly improved by Bacopa in this study. As aforementioned,
this contrasts with the findings of Stough et al. (2001) who found an improvement in
proactive interference, but not retroactive interference.
As well as concurring with human trials, this study’s finding of improved memory
acquisition and consolidation concurs with earlier animal studies. For example, Singh &
Dhawan (1997) demonstrated improved acquisition, consolidation and retention of three
newly learnt behaviours in rats. Additionally, it is interesting to note that the
improvement in auditory-verbal learning demonstrated by the current study supports the
reputed ancient usage of the herb for helping Vedic scholars memorise lengthy
scriptural hymns (Hackman, 1998). Such memorisation exemplifies an activity that is a
function of auditory-verbal memory and learning.
The results obtained in the AVLT in this study demonstrate that Bacopa improves
verbal memory in non-demented older persons. It is verbal memory that is impaired
early in AD, often years prior to diagnosis, with deficits in acquisition and retention of
new information evident from the onset of the disease (Lezak et al., 2004:214).
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Learning (acquisition) and delayed recall are parts of memory that are sensitive to
ageing effects as well as to AD (Petersen, 1992). Tests that measure delayed recall are
the most sensitive tests to detect the effects on memory of both normal ageing and AD
(Albert, 2002). Hence, benefits detected in delayed recall and acquisition in the current
study of healthy older people has implications that Bacopa may hold benefits for AD
sufferers as well. Future research to establish the efficacy of Bacopa for cognitive
improvement in early AD patients would thus be warranted.
The current trial found that beneficial effects of Bacopa were apparent after 12-weeks
duration. This, in concurrence with other human trials (Stough et al., 2001; Roodenrys
et al., 2002; Negi et al., 2000; Sharma et al., 1987), supports the notion that longer term
administration of Bacopa is required for its effects to become apparent. Acute
administration (2 hours) did not produce measurable cognitive effects in one study
(Nathan et al., 2001), and in Stough et al.’s study effects were found only at the 12week follow up and not at the 5-week follow-up. Likewise, in Negi et al.’s (2000) study,
significant improvement in memory tasks occurred at 12-weeks, but not at 4 or 8-weeks
of Bacopa administration. An extra follow-up visit in the current study, at the 6-week
mark, would have helped to verify the benefits of chronic over acute administration;
however availability of resources was a constraining factor.
7.3.2 Rey-Osterrieth Complex Figure Test (CFT) and Trail
Making Test (TMT):
While the current study demonstrated that Bacopa facilitates memory acquisition and
retention on an auditory-verbal learning test (the AVLT), the effects were not
significantly greater than placebo on tests assessing visuo-spatial memory, i.e. the CFT
and the TMT. In the CFT in both the 3-minute recall and 30-minute recall tasks, and in
TMT parts A and B, both placebo and Bacopa groups performed better at the 12-week
end-of-trial session than at baseline, with no significant differences between the groups.
Better performance for the whole sample on the CFT and TMT may reflect practice
effects, as the same CFT figure and the same TMT task were used at both baseline and
end-of-trial testing sessions, (unlike the AVLT test in which an equivalent alternate
word list was used at the follow-up visit). Parallel test figures are available for the CFT
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(Lezak et al., 2004:537-40), whereas in the TMT a parallel form is not feasible as it
comprises alphabet and number joining tasks. This must be considered a limitation of
the current study as practice effects may constitute a threat to internal validity, although
the inclusion of a control group attenuated this threat to some degree (Polgar & Thomas,
1995:56-61).
As discussed in the results section, there was also an inexplicable difference between
the two treatment groups means at baseline on the CFT only. The group means were
normally distributed and the difference was not accountable for by effects of gender,
age, or education. The reason for the difference remains unaccounted for and could have
indicated a difference in a variable not measured, for example eyesight or motor skills,
(as visual-motor but not audio-verbal tasks showed group difference). Retrospectively,
assessment of visual and auditory acuity would have been pertinent data to collect in the
pre-trial screening session.
7.3.3 The Memory Complaint Questionnaire (MAC-Q)
The MAC-Q scores showed subjective improvement in memory in both active and
placebo groups, however, the scores did not show any difference between groups. This
may reflect an improved attitude to memory because of increased attentional monitoring
of it due to study participation, that is, a Hawthorne effect; or it may reflect a desire to
give the researcher positive feedback, that is, a Rosenthal effect. These effects were
controlled for in this study by double-blinding and the use of a control group.
7.4 Possible mechanisms of action for observed effect of
Bacopa
Free radical damage impairs the function of neurons and is associated with the cognitive
deterioration seen in neurological disease (Halliwell & Gutteridge, 1985). The brain is
particularly susceptible to oxidative damage because it is very metabolically active (thus
high oxygen consumption), has high levels of iron (a pro-oxidant) and is a lipid rich
organ with high levels of unsaturated fat (prone to lipid peroxidation). The antioxidant
activity of Bacopa has been reported in a number of laboratory studies (Tripathi et al.,
1996; Bhattacharya et al., 2000; Sairam et al., 2001; Sumathy et al., 2001, 2002; Russo
et al., 2003a, 2003b). Bacopa’s antioxidant action and free radical scavenging activity,
especially in memory related structures in the brain including the hippocampus
65
(Bhattacharya et al., 2000), as well as astrocytes (Russo et al., 2003b), may explain
some of the memory improvement effect seen in the current study.
In addition to antioxidant effects, the memory facilitation effects found in the current
study may be due to enhanced cholinergic modulation in the central nervous system.
Bacopa has been shown to improve cholinergic function and enhance levels of
acetylcholine (ACh) in rat models of Alzheimer’s disease (Bhattacharya, et al., 1999;
Das et al., 2002). In the Bhattacharya et al. study, Bacopa improved induced cognitive
deficits and also countered colchicine-induced reductions of acetylcholine, choline
acetyltransferase activity and muscarinic cholinergic receptor binding in the
hippocampus. Das et al. demonstrated a dose dependent decrease in the enzymatic
breakdown of ACh in neuronal synapses. Furthermore, in an early study, Dey et al.
(1964) reported that marked hypotensive and bradycardic effects observed in cats given
Bacopa intravenously were partly modified by atropine- suggesting a cholinergic effect
of Bacopa.
Cholinergic neurotransmission plays a crucial role in memory function- it is required for
synaptic modification processes involved in long term memory formation in the
hippocampus (Hasselmo & Bower, 1993). A moderate decrease in cholinergic function
is associated with ageing, and a dramatic depletion of ACh is a feature of Alzheimer’s
disease (Trollor & Valenzuela, 2001). This is the rationale for the use of
acetylcholinesterase (AChE) inhibitors which can help to improve symptoms of
dementia in early stages of the disease. The cognitive benefits observed in the current
study may thus find application in Alzheimer’s disease, and a clinical trial of the effects
of Bacopa on dementia would seem worthwhile.
Beyond its antioxidant and cholinergic actions, Bacopa may act on the brain in other
ways as yet to be elucidated. The research thus far supports a nootropic action (i.e. nonspecific facilitation of cognitive function), rather than either a stimulant or sedative
action in the central nervous system (Singh et al., 1988). Furthermore, increased levels
of hippocampal protein kinase activity and enhanced protein levels have been reported
by Dhawan and Singh (1996). This is relevant because protein kinases are actively
involved in the synaptic modulation which accompanies long term potentiation (LTP) in
the hippocampus. Extensive research in this area of synaptic plasticity is providing a
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physiological basis underpinning important mechanisms of memory and learning
(Carlson, 2002:360-367). The research showing protein kinase activity for Bacopa is
promising but remains to be replicated, and more research is needed to further elucidate
possible mechanisms of action for the cognitive enhancing effects observed in this trial.
7.5 Side-effects
There were significant GIT side-effects reported in the current trial, with 45% of the
Bacopa group reporting at least one GIT effect, compared to only 5% of the placebo
group reporting any GIT effect. The GIT effects reported by the Bacopa group consisted
of increased stool frequency (15/49; 30%), nausea (9/49; 18%) and abdominal cramps
(8/49; 16%).
This finding contrasts with much of the literature on Bacopa; for example a doubleblind, placebo-controlled toxicological study in which bacosides were administered to
healthy male volunteers for one month demonstrated an absence of any side-effects
(Singh & Dhawan, 1997). Recent human studies of Bacopa have either not documented
any side-effects or reported an absence of them, with the exception of the Stough et al.
study (2001) which reported the occurrence in the Bacopa vs. placebo group of the
following symptoms: nausea (18% vs. 4%), dry mouth (23% vs. 16%) and muscle
fatigue (14% vs. 4%). Roodenrys et al. (2002) reported one adverse gastrointestinal
effect (unspecified) of Bacopa. Additionally, one early human trial of 24 patients aged
7-34 years, reported that 20% of patients receiving a crude aqueous extract of Bacopa
(50g fresh plant decocted in water, taken once daily), experienced abdominal pain and
‘slight gastro-intestinal disturbance’ although the exact nature of the disturbance was
not delineated by the authors (Mukherjee & Dey, 1966).
The side-effects observed in the current study cannot be put down to excessive dosage
as the dosage used was equivalent to 6g of dried herb material daily, this being in
accordance with the traditional recommended dosage regimen of 5-10g of the powdered
dried herb daily (Kapoor, 1990:61), as well as being the dosage recommended by the
manufacturer and that used in other human studies. Nor were the effects due to heavy
metal or microbiological contamination as analytical testing was carried out on the
study drug by the manufacturer, and excluded these possibilities.
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The observed side-effects may have been related to the saponins in Bacopa. As
previously discussed, Bacopa’s main active constituents are its saponins. Saponins are
glycosides (i.e. plant constituents which yield sugar on hydrolysis), that are of two
types- steroidal and triterpene (Lacaille-Dubois & Wagner, 1996). These are widely
distributed throughout the plant kingdom and occur in many foods and beverages. Mills
and Bone caution that herbs with high saponin content can irritate the gastric mucosa
(2005:252). In the upper digestive tract the gastric mucosal irritant effect has been
linked to a reflexive expectorant action, (probably mediated via the vagal nerve),
characteristic of saponin-rich expectorant herbs (which are also emetic in higher doses)
(Mills & Bone, 2000: 45).
Saponins interact with cell membranes by binding with sterols to create ‘pore-like’
openings in them; in red blood cells this eventually causes rupture and hence
haemolysis (Gee & Johnson, 1988). When this happens in the small intestine, an
increase in intestinal permeability can eventuate which may disrupt function and
absorption, as has been shown to occur in rat small intestine (ibid.). Saponins are
poorly absorbed in the digestive tract and usually then, only the aglycone (i.e.
sapogenin) component, hence the aforementioned haemolytic reaction will only occur
with injected and not orally ingested saponins (Mills & Bone, 2000:43). Thus saponins
can be safely ingested, though may react with the GIT mucosa.
It is feasible that one of the contributing causal factors of the GIT side-effects observed
in this trial was the high concentration of saponins in the herbal extract used due to the
standardisation process applied in its manufacture. The standardisation process in herbal
medicines ensures consistently high levels of the nominated active constituent/s by
measuring and maintaining levels of chemical marker compounds (Mills & Bone,
2000:123-4). Notably, minimum but not maximum amounts of marker compounds are
stipulated. Given the high level of saponins (Bacosides) in the study drug used- which
was standardised to contain at least 40%- coupled with a high concentration of the herb
per tablet (one 300mg tablet is equivalent to 6g of dried herb), it is postulated that this
resulted in a very high saponin content per tablet which may have caused GIT irritation,
whereas a less concentrated traditional extract may not have been enough to elicit a
reaction.
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Another important possible reason for the observed side-effects of Bacopa is that its
cholinergic action, as demonstrated in animal models (Das et al., 2002; Bhattacharya et
al., 1999; Dey et al., 1964), may be mediating adverse effects on the GIT, a reaction that
is a well documented side-effect of cholinergic therapy such as AChE inhibitor
medications used in dementia (Small et al., 1997; Flicker, 1999).
The neurotransmitter ACh is found centrally in the brain and spinal cord, peripherally in
skeletal muscle junctions, in ganglia of the autonomic nervous system (ANS), and in
organs supplied by the parasympathetic branch of the ANS (Carlson, 2002:107). AChE
is the enzyme in postsynaptic membranes which breaks down ACh. Inhibitors of this
enzyme thus cause the accumulation of ACh in synapses, prolonging its effects and
stimulating cholinergic transmission throughout the central and peripheral nervous
systems. GIT side-effects are caused both by parasympathomimetic effects- increased
tone, peristalsis and secretions of the stomach and intestines, and by motor effectsnausea, vomiting, belching, abdominal cramps and increased bowel movements (Koelle,
1975: 467-470).
The side-effects noted in the current study could thus all be explained by a cholinergic
effect of Bacopa. In addition to having cautionary implications for Bacopa usage, these
observations also lend support to the hypothesis that Bacopa has a cholinergic effect in
humans, and that the cognitive enhancing effects are, at least in part, mediated via
enhanced cholinergic modulation.
Finally, regarding the side-effects observed in this study, it is noteworthy that the
findings are in accordance with occasional traditional references to Bacopa as having a
laxative and even a mild purgative effect (Sivarajan, 1994: 97; Macmillan, 1991:424),
and an effect of diuresis, especially when urinary retention is accompanied with
constipation (Kapoor, 1990:61), (notably – both diuresis and laxation can be elicited by
cholinergic stimulation). Singh and Dhawan (1982) reproduce and translate Sanskrit
text from a 16th century Ayurvedic medical treatise- the Bhavprakasa Varg-Prakaranawhich, significantly, lists laxation amongst Bacopa’s actions.
This raises an important issue concerning traditional versus modern usage of plant
medicines which merits mention here. In Ayurvedic medicine, Bacopa is not used
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singly, but rather in complex formulae, with specific combinations indicated for various
pathologies and for various individual ‘constitutional’ types. For example, other herbs
in a Bacopa containing formula might attenuate GIT irritant effects. Furthermore,
people who react to Bacopa might be the type of person (constitution) for whom it
would not be indicated or prescribed according to Ayurvedic tradition. This raises the
interesting question of how we can integrate traditional knowledge of botanical actions
into the modern health care context when the wisdom on which it is based is not fully
understood or appreciated- can the knowledge be fully translated without this
underpinning basis? This is a question that warrants much consideration, however it is
outside the scope of the current study.
In this context, the reductionist methodology employed in trials such as the present one,
may not truly reflect the potential for herbal medicines like Bacopa, when applied in
their traditional context. However, the testing of complex formula brings in
confounding variables to the extent that such a trial would be methodologically flawed.
This issue (amongst others) presents a dilemma for complementary medicine research,
which as yet remains unresolved.
7.6 Limitations of the current study
A number of limitations are apparent in the current trial and are summarised below.
Firstly, a broader range of neuropsychological tests could have been used to elicit more
information about cognitive function. The neuropsychological assessments used were
far from exhaustive. Some widely used memory tests are not available to nonpsychologists and were also cost-prohibitive for this study, for example the Wechsler
Scales of Memory and Intelligence, (or component tests), are commonly included as a
core instrument in memory and cognitive testing (Lezak et al., 2004:480).
Resources available in this study restricted test selection to those that were firstly
available to the non-psychologist and secondly, affordable on a limited budget. Whilst
appropriate and broad spectrum, testing was far from exhaustive and could have been
expanded to include for example, a test of prose recall which imitates closely the
demands on memory of everyday events such as conversations, news items and other
media communications (Lezak et al., 2004:414). Furthermore, the use of single tests for
verbal and visual memory may not be a thorough enough measure on their own. For
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example, in one study in which different verbal memory tests were compared, high
levels of variability between tests was demonstrated, suggesting that a single test should
not be relied upon as a measure of verbal memory (Macartney-Filgate & Vriezen,
1988).
A second limitation of the current study was that sensory deficits are common in older
age groups and could have affected test performance. A common impairment in elderly
people is sight and hearing deficits, which could directly affect visual and verbalauditory test performance. In hindsight, visual and auditory acuity should have been
measured as part of the screening procedure, and use of visual or auditory aids
documented. Patient information should also have included that eyeglasses or hearing
devices should be brought in to memory assessment sessions. Furthermore, marked
auditory and visual deficits could have been incorporated into the exclusionary criteria
for study participation.
A third limitation of the current study is that a 6-week follow-up neuropsychological
assessment was unable to be included due to lack of resources. Hence assessment of
memory occurred only at baseline and at end-point (12-weeks). A 6-week measure
would have provided useful information about the time period required for Bacopa to
achieve an effect. Likewise, a 4-week post-trial assessment (at 16-weeks) would have
been worthwhile to assess whether the benefits achieved were maintained after finishing
Bacopa.
A fourth limitation of the current study is that the group baseline difference on CFT
scores remains unresolved. As previously discussed, this difference could not be
accounted for by differences on any independent variables including gender, age, or
education. Nor was inter-rater reliability an issue because the task was scored by the
same neuropsychologist. There could have been a difference between groups in a
variable not measured, for example acuity of eyesight (the CFT being a visual task), or
level of agility (as motor skills are required on the CFT). Alternatively, the Bacopa
group may have had better visual memory at baseline, (in which case those with better
visual memory might benefit more from Bacopa than those with poorer visual memory).
This issue remains unresolved.
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A fifth limitation of the study is that whilst for the AVLT an alternate word list was
used for the 12-week end-of-trial assessment, this was not the case for the CFT and the
TMT in which the same forms were utilised for pre and post testing. Thus, practice
effects may have occurred on these tests, which would limit the interpretation of
significant findings on these tasks, had any had been found. Practice effects are
especially evident in memory tests- so much so that their absence may point to
cognitive deficits (Lezak et al., 2004: 114). The effect can be eliminated for verbal tests
with the use of parallel forms on repeated testing; however with visuospatial tests there
will still be some practice effects even with the use of an alternate form because
learning about how to perform the task occurs (as well as learning the actual content)
(Lezak et al., 2004: 415). Practice effects on the CFT and TMT were evidenced by the
improved scores after 12-weeks in both treatment and placebo groups. Alternative
figures have been developed for the CFT; the most widely used being the Taylor figure,
though scoring is generally a little higher on this figure than on the CFT (Lezak et al.,
2004: 458). The use of a control group in the current study controlled for practice
effects, however alternate forms on the CFT would have strengthened the study.
Lastly, another limitation noted in the current study is the failure to adjust for the use of
multiple dependent variables. Neuropsychological assessment cannot be achieved with
singular outcome measures, necessitating the use of multiple measures. The large
number of analyses performed may have increased the risk of a type one error, that is, of
finding a significant effect when none exists. The current study did not adjust for
multiple measures. The alpha value could have been set at .01 rather than .05 to
counteract this increased risk.
7.7 Recommendations arising from the study
One outcome of this study is recommendations to help counteract the GIT side-effects
observed with Bacopa administration. It is advised that Bacopa doses equivalent to 6g
of dried plant should be given in divided doses; and that manufacturers might thus
ideally restrict the amount of herb per tablet to 3g (dry weight equivalent). Enteric
coating of Bacopa tablets would protect the upper GI mucosa from exposure to the
saponins, and thus would seem warranted. It is also suggested, in the light of these
findings, that Bacopa tablets be taken with food, again to help buffer the GI mucosa
72
from the irritant effect of saponins. Furthermore, it would be pertinent for further
research on Bacopa to see if the side-effects observed in this study are replicable.
Further research to establish cholinergic effects in humans and to elucidate other
possible mechanisms of action is warranted. Human trials of Bacopa in the dementia
population would seem warranted to see if the cognitive enhancement observed in nondemented older persons might also benefit dementia sufferers, particularly given the
support for evidence of cholinergic activity observed, as well as documented antioxidant
activity. Effective pharmacological treatment of dementia remains largely elusive and
there is a need to explore all possible therapies. This study has demonstrated that
Bacopa produces cognitive benefits in older people, lending weight to previous
evidence of cognitive function enhancement. These demonstrated nootropic effects may
be of benefit to dementia sufferers too.
Because early intervention is likely to be the most effective point of intervention in
neurodegenerative pathologies, and because delaying onset of dementia would have
such a dramatic impact as discussed in chapter 3, then trials of Bacopa in people
meeting criteria for Mild Cognitive Impairment (MCI) would also be indicated, in an
effort to reduce or delay progression to dementia.
In any further studies looking at verbal and visual memory, it is recommended that
visual and auditory acuity testing is included at screening to account for potential effects
of deficits. Participants should also be advised to bring visual and hearing aids to
assessment sessions.
Additional neuropsychological testing is advisable in future clinical studies to give a
broader appraisal of the potential effects of Bacopa. Additionally, it would be pertinent
to employ alternative figures for the CFT if used.
All of the human studies on Bacopa have looked at effects of up to 12-weeks duration
of administration and doses of 300mg/day. It would be interesting for further studies to
assess the effects of longer administration periods, and different dosage regimens.
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A final recommendation is that when non-psychologists design future clinical trials
involving assessment of neuropsychological function, it is important that budgeting
should factor in adequate resources to cover the costs of the neuropsychological tests
employed as well as the neuropsychological expertise required to administer them- both
of these can be very costly.
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8. CONCLUSION
This thesis reported the results of a 12-week double-blind, placebo-controlled clinical
trial of the effects of Bacopa monnieri on memory performance in healthy older
Australians. The purpose of this trial was to determine whether the beneficial cognitive
effects of Bacopa as reported in earlier studies were replicable in the elderly, as this is
the demographic most affected by memory difficulties; and also to document the
presence or absence of adverse events.
Demographically, Australia, along with other nations globally, has an ageing
population. Neurological illnesses are widely referred to as the new epidemic, as longer
life-spans allow more neuropathology to emerge. Dementia rates in the Western world,
and indeed globally, are high and on the increase. This is of great concern as it places
escalating demands on limited health care resources, as well as causing enormous
personal suffering. Non-pathological memory loss in the aged population also has a
very high incidence, which has been reported as occurring in almost half of the over 65years age group (Small, 2002).
The identification of agents that can improve neurological health and cognitive function
is an important endeavour, firstly because of the potential to improve quality of life for
sufferers of cognitive impairment and their families, and secondly, to reduce the burden
of neurological illness on health care resources. The exploration of medicines used in
traditional cultures for improving neurological function seems a valid starting point in
the quest for treatment strategies, especially because highly effective pharmacological
treatments for cognitive decline do not exist. Evidence is accumulating for the cognitive
benefits of some therapies found in the complementary medicine field, such as various
nutritional supplements and herbal medicines, especially in relation to preventing and
reducing neurological oxidative damage and improving neurotransmission.
Bacopa monnieri is a herb with a long traditional usage in Ayurvedic medicine for its
beneficial effects on mental functioning. This traditional usage is supported by both preclinical and clinical research. This study tested the hypothesis that Bacopa would
75
improve memory in healthy older Australians. This extended previous findings that
have shown evidence of a beneficial effect on memory in younger age groups. It was
also postulated that the use of Bacopa would not be associated with any side-effects.
A clinical trial was carried out to assess the effects of 12-weeks administration of
Bacopa monnieri (300mg/day) on memory in people over 55-years of age. Primary
outcome measures were well validated neuropsychological tests to objectively measure
audio-verbal and visual memory, and a memory complaint questionnaire to measure
subjective memory complaints. The results demonstrated that Bacopa versus placebo
significantly improved memory acquisition and retention in older Australians. This
concurs with findings from previous human and animal studies, as well as supports
traditional Ayurvedic claims and uses.
Contrary to a postulated absence of side-effects, Bacopa’s use was associated with GIT
side-effects, specifically increased bowel movements, nausea and abdominal cramping.
These side-effects have been infrequently reported in previous literature, with most
literature reporting an absence of side-effects. These symptoms may have been due to
either GIT irritation by the saponin component of the herb, or to possible cholinergic
stimulation of autonomic and motor responses in the GIT, or to a combination of both
of these factors. And whilst these factors offer the most likely explanations for the
observed side-effects, other, as yet not understood mechanisms must also be considered.
This study’s replicated findings of beneficial effects on human memory have promising
implications for Bacopa’s potential use in dementia. This is especially so, given its
demonstrated antioxidant and cholinergic actions, because dementia is associated with
both oxidative damage and depletion of acetylcholine. The side-effects observed in this
study lend further weight to previous findings of a cholinergic effect of Bacopa. Animal
studies have demonstrated a cholinergic action, though more research is needed to
further establish a cholinergic effect for Bacopa in humans, and to identify other
possible mechanisms of action as well. Given that even modest postponement of
dementia symptoms would have enormous benefits for sufferers and for society, the
identification of cognitive enhancing agents is an important pursuit. Thus, a clinical trial
of Bacopa in dementia patients would seem a worthwhile extension of the current study.
76
Many older people report memory deficits and many look to complementary medicines
for solutions to health problems, including cognitive enhancement. Research such as the
current study contributes efficacy and safety data that will assist Australians to choose
more effective therapies and may identify agents that can improve quality of life and
ultimately reduce the health care costs associated with degenerative illnesses. An
evidence basis for complementary medicine usage will enable these therapies to take
their place alongside mainstream medical approaches in the interest of better health care
for all.
77
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91
Appendix I: Participant instruction sheet and record booklet
Clinical Trial: ‘Does Bacopa monnieri improve memory in older
Australians?’
Participant Instruction Sheet and Record Booklet
Participant name: ______________________________________
Follow up appointment: _________________________________
Instructions:
•
Take one tablet daily after food
•
Store in a cool dry place
•
Bring container and any left over tablets to next appointment
•
Record any comments, or possible side effects in comments section
•
Please contact Annette Morgan with any questions or comments phone: (02)
6620 3155 or [email protected]
Annette Morgan and Dr John Stevens
School of Nursing & Health Care Practices
92
Participant record booklet: please complete daily and submit at last
appointment (end of study).
Day
number
Date
Tablet taken
Comments, record any symptoms or
(tick)
possible side effects experienced
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
93
Day
number
Date
Tablet
taken (tick)
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
Well done, two thirds there!
94
Day
number
Date
Tablet
taken (tick)
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
END OF TRIAL!
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Appendix II: Human research ethics committee approval
SOUTHERN CROSS UNIVERSITY
~ MEMORANDUM ~
To:
J. Stevens/A. Morgan
NHCP
[email protected]
[email protected]
From:
Secretary, Human Research Ethics Committee
Date:
17 September 2004
Project:
Does Bacopa monnieri improve cognitive function in Age
Associated memory Impairment (AAMI)
Status:
Protocol change and renewal of project.
New Approval Number
ECN-04-141
HUMAN RESEARCH ETHICS COMMITTEE (HREC)
At the meeting of the HREC on 13 September, the change of protocol to your project to
the population of participants has been noted by the Committee. The renewal of this
project has also been approved and a new approval number issued.
In the Informed Consent information, you do not require the statement about parent or
guardian if subject is under 18 years of age, as the population is the ‘elderly. Please
correct this Informed Consent carefully before it is given to participants.
96
The approval is subject to the standard conditions of approval below.
Standard Conditions (in accordance with National Health and Medical Research
Council Act 1992 and the National Statement on Ethical Conduct in Research Involving
Humans):
1.
That the person responsible (usually the Supervisor) provide a report every 12
months during the conduct of the research project specifically including:
2.
(a)
The security of the records
(b)
Compliance with the approved consents procedures and documentation
(c)
Compliance with other special conditions.
That the person responsible and/or associates report and present to the Committee
for approval any change in protocol or when the project has been completed.
3.
That the person responsible and/or associates report immediately anything that
might affect ethical acceptance of the research protocol.
4.
That the person responsible and/or associates report immediately any adverse
effects on participants.
5.
That the person responsible and/or associates report immediately any unforeseen
events that might affect continued ethical acceptability of the project.
6.
That subjects be advised in writing that:
“Any complaints or queries regarding this project that cannot be answered by the
person responsible for this research project should be forwarded to:
Ms Suze Kelly, Secretary, HREC.
Graduate Research College, Southern Cross University
PO Box 157, Lismore, 2480
Ph: (02) 6626 9139 Fax: (02) 6626 9145 Email: [email protected]”
97
Suzanne Kelly
Secretary, HREC
(02) 6626 9139
[email protected]
Dr Baden Offord
The Chair, HREC
Ph: (02) 6620 3162
[email protected]
98
Appendix III: Participant consent form and information sheet
PARTICIPANT INFORMATION SHEET
A clinical study assessing the effects of Bacopa monnieri
on memory performance in older people
Purpose of Study:
The School of Nursing and Health Care Practices invites you to participate in a
study to assess whether a herbal medicine called Bacopa monnieri improves
memory in people over the age of 55 years.
This study is being carried out by Annette Morgan, as part of a Masters of
Health Science research thesis through Southern Cross University. The
supervisor of the research is Dr John Stevens, Lecturer, School of Nursing,
Southern Cross University. Approval for the study has been given by Southern
Cross University’s Human Research Ethics Committee.
Aims of the Study:
Bacopa monnieri, popularly known as Brahmi, is a herb with an ancient
reputation of improving mental functions such as memory and concentration,
and it is used as a general ‘brain tonic’. We are interested to see whether this
herb will improve aspects of memory in the over 55 age group, thereby
improving quality of life.
Procedures to be followed:
The study will involve three one hour visits to the Southern Cross University
Natural Medicine Clinic located at 6 Industry Drive, East Lismore. The first visit
will consist of an initial consultation with the researcher, who will take a brief
medical history and perform brief screening of memory, mood and cognition. If
99
you meet the entry criteria of the study you will be booked in for a more
thorough memory assessment with a research assistant trained in psychology.
Participants will be randomly allocated into two groups. Following the first
memory assessment (second visit) which provides a baseline measure of
memory function, one group will be given Bacopa monnieri tablets, and the
second group will be given identical placebo tablets.
Dosage is one tablet daily after food for 12 weeks. Neither participants nor the
researchers will know which participants are on Bacopa or placebo tablets, until
the end of the trial. At the end of week 12, participants will come to the
university for a third and final visit to have the same memory assessment
repeated. Scores obtained in the two memory assessments will be analysed.
This should provide an objective assessment of the efficacy of the herb.
Possible discomforts and risks
Bacopa monnieri is approved for over the counter sale in Australia, and is freely
and widely available in retail outlets. It is a well researched herb, with a long
history of traditional usage and has an excellent safety profile. One four week
clinical trial to assess safety demonstrated an absence of side effects. Thus, it
is unlikely that you will experience any adverse effects. It is recommended that
the tablets be taken after food.
Although it is unlikely that you will experience any adverse effects from taking
Bacopa, please discontinue usage in the event any occur and notify the study
co-ordinator immediately.
Confidentiality:
The researchers accept responsibility to maintain anonymity and confidentiality,
and will not disclose any information that will identify participants. All data
obtained will be stored in a locked cupboard in offices of the researcher at
Southern Cross University. Only those directly involved in the research will have
access to the data.
100
Freedom of Consent:
If you agree to participate, you are free to withdraw your consent and to
discontinue participation at any time. However, informing us of your decision
would be appreciated.
Inquiries:
We are available to answer any questions or comments you may have at any
time. Please contact:
Study Co-ordinator:
Ms Annette Morgan ph: (02) 6620 3155, email: [email protected]
If unavailable, please contact:
Study Supervisor:
Dr John Stevens: (02) 6620 3306
Any complaints or queries regarding this research that cannot be answered by
the researchers (above) should be forwarded to:
Mr John Russell
Graduate Research College
Ph: (02) 6620 3705, Fax: (02) 6626 9145, email: [email protected]
101
PARTICIPANT CONSENT FORM
Name of Project: ‘Does Bacopa monnieri improve memory in older people?’
I have read the information sheet and agree to participate in this study.
Name of Participant: ____________________________________________
Signature of Participant: _________________________________________
Date: _________________________________________________________
Name of witness (who shall be independent of the project)
I,____________________________________________________ certify that the terms
of the form have been verbally explained to the subject, that the subject appears to
understand the terms prior to signing the form, and that proper arrangements have been
made for an interpreter where English is not the subject's first language. On advice
given I asked the subject if she/he needed to discuss the project with an independent
person before signing and she/he declined (or has done so).
Signature of Witness
Date___________
I certify that the terms of the form have been verbally explained to the participant, that
the participant appears to understand the terms prior to signing the form, and that
proper arrangements have been made for an interpreter where English is not the
participants first language.
Signature of Researcher: __________________________Date: _______________
102
Appendix IV: Clinical report form
Master of Health Science
Research Thesis
‘Does Bacopa monnieri improve memory in older people?’
PARTICIPANT DATA BOOKLET
Participant code:______________________
Annette Morgan and Dr John Stevens
School of Nursing & Health Care Practices
103
CLINICAL REPORT FORM
1 Demographic Information
Name
Date
Address
Phone
DOB
Age (yrs)
Marital status
Gender
Education (yrs)
Occupation
2 Medical History
Head Injury/ Infection/ Inflammation
Neurological disorder
TIA
Stroke
Psychiatric Illness
Cardiovascular disease
Renal disease
Hepatic disease
Diabetes
Haematological disorder
Endocrine illness
Malignancy
Psychotropic drug use
Alcohol / drug use
Other Illness
3 Current medications, herbal & nutritional supplements
4 Physical examination
BP
Pulse
Respiratory rate
Temperature
Urine Analysis
Notes
104
5. Modified Hachinski Scale (Rosen et al., 1980)
Characteristic
Point score
Abrupt onset of symptoms
2
Stepwise deterioration
1
Somatic complaints
1
Emotional incontinence
1
Hypertension history / current
1
Stroke history
2
Focal neurological symptoms
2
Focal neurological signs
2
Total score=
(Score of 4 or more suggests multi-infarct dementia)
6. Current memory/cognitive difficulties experienced:
Memory loss
Forgets recent events
Forgets things just said
Forgets names of people
Forgets words
Gets lost
Asks questions or tells story repeatedly
Confused about date or place
Cant do simple calculations
Cant understand what is read or said
Impairment of other cognitive functions
Anxiety or agitation
Paranoia
Delusions or hallucinations
Wandering
Disruptive behaviour
Incontinence
105
7. The Mini-Mental State Examination (Folstein et al., 1975)
NAME: ________________________________ DATE: ___________________
Orientation: (10 points)
What is the year?
What is the season?
What day of the week is it?
What is the month?
Can you tell me where we are? (residence or street name)
What city/ town are we in?
What state are we in?
What country are we in?
What are the names of two streets nearby?
What floor of the building are we on?
Registration: (3 points)
I am going to name three objects. After I have said them, I want
you to repeat them. Remember what they are because I am going
to ask you to repeat them again in a few minutes.
‘Apple.....Table......Penny’
Attention and calculation: (5 points)
Can you subtract 7 from 100, and then subtract 7 from the answer
you get and keep subtracting 7 until I ask you to stop?
Now I am going to spell a word forwards and I want you to spell it
backwards. The word is WORLD. W-O-R-L-D.
Recall: (3 points)
Now, what were the three objects I asked you to remember?
Language: (9 points)
What is this called (show watch)
What is this called (show pencil)
Now I would like you to repeat a phrase after me:
‘No ifs and or buts’
Read the words on this page then do what it says. (The page says
in large letters ‘CLOSE YOUR EYES’)
Take this paper in your right hand, fold the paper in half using
both hands and put the paper down using your left hand
Pick up the paper and write a short sentence on it. (Sentence must
have a subject and a verb and make sense)
Now copy the design that you see printed on the page. (Design is
interlocking pentagons. The result must have five-sided figures
with intersection forming a four sided figure).
Score
1
1
1
1
1
1
1
1
1
1
3
2
3
3
1
1
1
1
3
1
1
TOTAL: 30
106
CLOSE YOUR EYES
WRITE A SENTENCE:
107
8. The Hamilton Rating Scale for Depression
Ref: Hedlung & Vieweg, 1979; adapted by GlaxoWellcome, 1997
Participant Name:_________________________________________________
Date of Assessment_______________________________________________
For each item, write the correct score adjacent to item (only one response per item)
Score
______
______
______
______
______
______
1. DEPRESSED MOOD
0= Absent
1= Indicated only on questioning
2= Spontaneously reported
3= Communicates non-verbally through facial expression, posture,
voice, tendency to weep
4= Reports virtually only these feeling states in spontaneous verbal
and non-verbal expression
2. FEELINGS OF GUILT
0= Absent
1= Self reproach, feels he has let people down
2= Ideas of guilt or rumination over past errors or sinful deeds
3= Sees present illness as a punishment. Delusions of guilt.
4= Hears accusatory or denunciatory voices and/or experiences
threatening visual hallucinations
3. SUICIDE
0= Absent
1= Feels life is not worth living
2= Wishes he were dead, or any thoughts of possible death to self
3= Suicidal ideas or gesture
4= Attempts at suicide
4. INSOMNIA EARLY
0= No difficulty in falling asleep
1= Complains of occasional difficulty falling asleep- more than ½
hour
2= Complains of nightly difficulty falling asleep
5. INSOMNIA MIDDLE
0= No difficulty
1= Complains of being restless and disturbed during the night
2= Waking during night
6. INSOMNIA LATE
0= No difficulty
1= Waking in early hours of morning but goes back to sleep
2= Unable to fall asleep again if gets out of bed
108
______
______
______
______
______
______
______
______
7. WORK AND ACTIVITIES
0= No difficulty
1= Thoughts and feelings of incapacity, fatigue or weakness
related to activities, work or hobbies
2= Loss of interest in activities, hobbies or work
3= Decrease in actual time spent in activities or decrease in
productivity
4= Stopped work because of current illness/feeling state
8. RETARDATION: PSYCHOMOTOR (Slowness of thought and
impaired ability to concentrate; decreased motor activity)
0= Normal speech and thought
1= Slight retardation at interview
2= Obvious retardation at interview
3= Interview difficult
4= Complete stupor
9. AGITATION
0= None
1= Fidgetiness
2= Playing with hands, hair, etc.
3= Moving about, can’t sit still
4= Hand wringing, nail biting, hair-pulling, biting of lips
10. ANXIETY (PSYCHOLOGICAL)
0= No difficulty
1= Subjective tension and irritability
2= Worrying about minor matters
3= Apprehensive attitude apparent in face or speech
4= Fears expressed without questioning
11. ANXIETY (SOMATIC)
0= Absent
1= Mild
2= Moderate
3= Severe
4= Incapacitating
12. SOMATIC SYMPTOMS (GASTROINTESTINAL)
0= None
1= Loss of appetite but eats without encouragement
2= Difficulty eating without encouragement, reduction of food
intake
13. SOMATIC SYMPTOMS (GENERAL)
0= None
1= Heaviness in limbs, back, head. Aching, low energy, fatigability.
2= Any clear cut symptoms
14. GENITAL SYMPTOMS (loss of libido, impaired sexual
performance, menstrual disturbances)
0= Absent
1= Mild
2= Severe
109
______
______
______
______
______
______
______
______
15. HYPOCHONDRIASIS
0= Not present
1= Self-absorption (bodily)
2= Preoccupation with health
3= Frequent complaints, requests for help etc
4= Hypochondriacal delusions
16. LOSS OF WEIGHT
0= Not present
1= Probably weight loss associated with present illness
2= Definite weight loss reported
3= Not assessed
17. INSIGHT
0= Acknowledges being depressed and ill
1= Acknowledges illness but attributes cause to bad food, climate,
over-work, virus etc.
2= Denies being ill at all
18. DIURNAL VARIATION
A. Note whether symptoms are worse morning or evening
0= No variation
1= Worse in A.M.
2= Worse in P.M.
B. When present, mark the severity of the variation
0= None
1= Mild
2= Severe
19. DEPERSONALISATION AND DEREALIZATION (Such as
feelings of unreality; nihilistic ideas)
0= Absent
1= Mild
2= Moderate
3= Severe
4= Incapacitating
20. PARANOID SYMPTOMS
0= None
1= Suspicious
2= Ideas of reference
3= Delusions of reference and persecution
21. OBSESSIONAL AND COMPULSIVE SYMPTOMS
0= Absent
1= Mild
2= Severe
Total Score ___________
110
Appendix V: Neuropsychological test administration protocol
Timing of Test Administration
1. Complex Figure Test Copy Task (5-minutes)
2. Memory complaint questionnaire (MAC-Q) (3-minutes only)
3. Complex Figure Test 3-minute recall (5-minutes - unlimited)
4. RAVLT trials A1- A5, B1 and A6 (10-minutes)
5. Complete and/or discuss MAC-Q (10-minutes)
6. Trail A and Trail B
7. Complex Figure Test 30-minute Recall Trial (10-minutes)
8. Complex Figure Test Recognition Task
9. RAVLT Recall Trial = A7 (3-minutes)
10. RAVLT Recognition Trial (5-minutes)
RAVLT abbreviations
•
Repeated words= R
•
Repeated & self-corrected= RC
•
Questions whether repeated but unsure= RQ
•
Words not on list are errors= E
111
Appendix VI: Specification sheets for Bacopa and placebo
tablets
112
113
114
Appendix VII: Rey Auditory Verbal Learning Test (AVLT)
AVLT 1st Administration- baseline assessment (Lezak et al., 2004:422-426)
NAME: __________________________________DATE: ______________________
LIST A
1
2
3
4
5
LIST B
DRUM
DESK
CURTAIN
RANGER
BELL
BIRD
COFFEE
SHOE
SCHOOL
STOVE
PARENT
MOUNTAIN
MOON
GLASSES
GARDEN
TOWEL
HAT
CLOUD
FARMER
BOAT
NOSE
LAMB
TURKEY
GUN
COLOUR
PENCIL
HOUSE
CHURCH
RIVER
FISH
TOTAL
TOTAL
B
A
20 ′
Rec
115
Rey Auditory Verbal Learning Test Delayed Recognition Trial (1st administration)
The participant must respond Yes / No to each word that is read out according to
whether they think the word was on list A. The examiner circles every word that has a
Yes response.
ANSWERS
Bell (A)
Home (sa)
Towel (B)
Boat (B)
Glasses (B)
Window (sa)
Fish (B)
Curtain (A)
Hot (pa)
Stocking (sb)
Hat (A)
Moon(A)
Flower
Parent (A)
Shoe (B)
Barn (sa)
Tree (pa)
Colour (A)
Water (sa)
Teacher (sa)
Ranger (B)
Balloon (pa)
Desk (B)
Farmer (A)
Stove (B)
Nose (A)
Bird (B)
Gun (B)
Rose (spa)
Nest (spa)
Weather (sb)
Mountain (B)
Crayon (sa)
Cloud (B)
Children (sa)
School (A)
Coffee (A)
Church (B)
House (A)
Drum (A)
Hand (pa)
Mouse (pa)
Turkey (A)
Stranger (pb)
Toffee (pa)
Pencil (B)
River (A)
Fountain (pb)
Garden (A)
Lamb (B)
KEY
List A words = ________(A)
List B words = (B)
s = word with a semantic association to a word on List A or List B
p = word phonemically similar to a word on List A or List B
116
Appendix VIII: Rey Auditory Verbal Learning Test (AVLT)
alternate form for endpoint assessment
AVLT 2nd administration: week-12 assessment (alternate word list by JonesGotman, Szilkas & Majdan, cited in Lezak et al., 2004: 423)
PATIENT NAME: ______________________________DATE:_________________
LIST A
1
2
3
4
5
LIST B
VIOLIN
ORANGE
TREE
ARMCHAIR
SCARF
TOAD
HAM
CORK
SUITCASE
BUS
COUSIN
CHIN
EARTH
BEACH
KNIFE
SOAP
STAIR
HOTEL
DOG
DONKEY
BANANA
SPIDER
RADIO
BATHROOM
BUCKET
CASSEROLE
HUNTER
SOLDIER
FIELD
LOCK
TOTAL
TOTAL
B
A
20 ′
Rec
117
Rey Auditory Verbal Learning Test Delayed Recognition Trial (2nd
administration- week 12)
The participant must respond Yes / No to each word that is read out according to
whether they think the word was on list A. The examiner circles every word that has a
Yes response.
ANSWERS
Rock (pb)
Star (sa)
Soap (B)
Television (sa)
Violin (A)
Corn (pb)
Peel (sa)
Frog (sb)
Hotel (B)
Beach (B)
Pear (sa)
Lock (B)
Dog (A)
Piano (sa)
Radio (A)
Tree (A)
Banana (A)
Orange (B)
Spider (B)
Bus (B)
Cork (B)
Toad (B)
Cousin (A)
Bucket (A)
Doctor
Bread
Uncle (sa)
Bathroom(B)
Soldier
Chest
Sofa (sb)
Earth (A)
Gloves (sb)
Scarf (A)
Knife (A)
Stair (A)
Hospital (sb)
Field (A)
Wife (sa)
Donkey (B)
Ham (A)
Grass (sa)
Armchair (B)
Train (sb)
Hunter (A)
Casserole (B)
Lunchbox (sb)
Blanket (pa)
Suitcase (A)
Chin (B)
KEY
List A words = ________(A)
List B words = (B)
s = word with a semantic association to a word on List A or List B
p = word phonemically similar to a word on List A or List B
118
Appendix IX: Rey-Osterrieth Complex Figure Test (CFT)
Ref: adapted from Osterrieth, 1944 cited in Lezak et al., 2004.
119
Appendix X: Rey-Osterrieth Complex Figure Test (CFT)
marking Sheet
Ref: Scoring system for CFT taken from Taylor 1959, adapted from Osterrieth, 1944
cited in Lezak et al., 2004.
Units
COPY
IMMEDIATE 30 MINUTE
RECALL
RECALL
1. Cross, upper left corner, outside of
rectangle
2. Large rectangle
3. Diagonal cross
4. Horizontal midline of 2
5. Vertical midline
6. Small rectangle, within 2 to the left
7. Small segment above 6
8. Four parallel lines within 2, upper left
9. Triangle above 2, upper right
10. Small vertical line within 2, below 9
11. Circle with 3 dots, within 2
12. Five parallel lines within 2 crossing 3,
lower right
13. Sides of triangle attached to 2 on right
14. Diamond attached to 13
15. Vertical line within triangle 13
parallel to right vertical of 2
16. Horizontal line within 13, continuing
4 to right
17. Cross attached to 5 below 2
18. Square attached to 2, lower left
TOTAL SCORE (out of 36)
Scoring:
Consider each of the units separately. Appraise accuracy of each unit and relative
position within the whole of the design. For each unit count as follows:
Correct
Distorted or incomplete
but recognisable
Absent or not recognisable
Maximum
Placed properly
Placed poorly
2 points
1 point
Placed properly
Placed poorly
1 points
½ point
0 points
36points
120
CFT scoring sheet continued. Use figure below to guide scoring.
121
Appendix XI: Trail Making Test (TMT) parts A and B
Ref: Reitan, 1958; test instructions from Spreen & Strauss, 1991.
TRAIL MAKING TEST- PART A
NAME: ............................................................................
DATE: .............................................................................
Sample: join numbers together in correct order without lifting pen from the
page, and in fastest time possible; e.g. 1 to 2 to 3 and so on until finished.
End
7
2
8
Begin
4
1
3
6
5
122
TRAIL MAKING TEST- PART A
123
TRAIL MAKING TEST- PART B
NAME: ...........................................................................
DATE: ............................................................................
Sample: join numbers and letters together in correct order without lifting pen
from the page, and in fastest time possible; e.g. from 1 to A to 2 to B to 3 to C
and so on until finished
End
4
A
D
Begin
B
1
2
C
3
124
TRAIL MAKING TEST- PART B
125
Appendix XII: Memory Complaint Questionnaire (MAC-Q)
From: Crook et al., 1992
Name: ....................................................................Date: .................................................
As compared to when you were in school, how would you describe your ability to
perform the following tasks involving you memory?
Much
Somewhat
About
Somewhat
Much
better now
better now
the same
poorer now
poorer now
(1)
(2)
(3)
(4)
(5)
1. Remembering the
name of a person just
introduced to you
2. Recalling
telephone numbers or
postcodes that you
use on a daily or
weekly basis
3. Recalling where
you have put objects
(such as keys) in your
home or office
4. Remembering
specific facts from a
newspaper or
magazine you have
just finished reading
5. Remembering the
items you intended to
buy when you arrive
at the grocery store or
pharmacy
6. In general, how
would you describe
your memory
compared to when
you were in high
school
TOTAL SCORE_______________________
126
Appendix XIII: Results of repeated measures analysis for all
variables
TASK
AVLT a1
AVLT a2
AVLT a3
AVLT a4
AVLT a5
AVLT b (interference list)
AVLT a6
AVLT a7 (delayed recall)
AVLT recognition hit rate
AVLT recognition false positives
AVLT true recognition rate
AVLT total learning a1-a5
AVLT retroactive interference
AVLT proactive interference
AVLT forgetting rate
CFT copy
CFT 3min recall
CFT 30min recall
MACQ
Trail Making Test A
Trail Making Test B
F
1.823
.894
2.348
13.204
6.094
.143
18.830
12.021
1.242
2.555
3.539
6.761
4.020
1.353
.365
.649
1.101
1.887
2.525
.038
1.280
df
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Error df
79
79
79
79
79
79
79
79
79
79
79
79
79
79
79
79
79
79
79
79
79
Sig.
.181
.347
.129
.000
.016
.706
.000
.001
.269
.114
.064
.011
.048
.248
.547
.423
.297
.173
.116
.847
.261
General Linear Model, Repeated Measures Analysis of Variance employing time as within subjects factor
and group as between subjects factor was used. F= Fisher value for significance of group contrasts. df
=degrees of freedom for the two treatment groups, error df=degrees of freedom for error. Sig.=one-tailed
significance. AVLT = Rey Auditory Verbal Learning Test, AVLTa1-a7 = repetitions of word list A
(possible range 0-15), AVLT b = interference word list B (possible range 0-15), AVLT rec = recognition
list hit rate (possible range 0-15) , AVLT recognition false positives (possible range 0-35), AVLT true
recognition rate = recognition list hit rate minus false positives, (possible range -35 to +15) , AVLT total
learning a1-a5 = total learning score (sum of trials a1 to a5, range 0-75), AVLT retroactive interference
score (trial a5 minus trial a6, possible range -15 to +15, lower scores = better performance, ), AVLT
proactive interference score (trial a1 minus trial b, possible range -15 to +15, lower scores = better
performance), AVLT forgetting rate (trial a6 minus trial a7, possible range -15 to +15, lower scores =
better performance); CFT = Rey-Osterrieth Complex Figure Test (possible range 0-36 on all tasks),
CFTcopy=copy task, CFT 3-minute recall task, CFT 30-minute recall task; MAC-Q = Memory
Complaint Questionnaire (possible range 7-35, lower scores = better performance); Trail Making Test A
and B scores=time taken to complete task (in seconds).
127

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