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Biogerontology

, Volume 13, Issue 3, pp 299–312 | Cite as

Evaluating the traditional Chinese literature for herbal formulae and individual herbs used for age-related dementia and memory impairment

  • Brian H. May
  • Chuanjian Lu
  • Louise Bennett
  • Helmut M. Hügel
  • Charlie C. L. Xue
Research Article

Abstract

Natural products are the basis of many systems of traditional medicine and continue to provide sources for new drugs. Ethnobiological approaches to drug discovery that have proven productive in the past include the investigation of traditional medical literatures. This study describes a broadly applicable method for locating, selecting and evaluating citations in the traditional Chinese herbal medicine literature of the dynastic period (until 1911) for specific symptoms or disorders. This methodology is applied to evaluate multi-herb formulae for age-related dementia and memory impairment. Of the 174 multi-herb formulae located in the searches, 19 were for disorders broadly consistent with amnestic Mild Cognitive Impairment (MCI) and/or Age Associated Memory Impairment (AAMI). These appeared in books written between c. 650 to 1911. Of the 176 herbs that appeared in these 19 formulae, those with the highest frequencies were tabulated and hierarchical cluster analysis was undertaken. Chinese pharmacopoeias were consulted to determine the botanical identity of the herbs and also which herbs within the formulas were specific for memory disorders. This study found that the top ten herbs, in terms of frequency of inclusion in multi-herb formulae specific for age-related memory disorders, were all listed in the pharmacopoeias for memory disorders and these formed three clusters. The herbs identified in this study may warrant further experimental and clinical evaluation both individually and in combination.

Keywords

Herbal medicine Drug discovery Natural products Text mining Dementia Memory impairment Ageing 

Abbreviations

AAMI

Age-Associated Memory Impairment

AD

Alzheimer’s disease

BCGM

Ben Cao Gang Mu ‘Materia Medica Classified by Section and Sub-section’

Chi dai

Traditional Chinese term that refers to dementia and similar disorders

CHM

Chinese Herbal Medicine

Jian wang

Traditional Chinese term that refers to forgetfulness or memory impairment

Lao nian chi dai

Modern Chinese term for senile dementia

MCI

Mild Cognitive Impairment

OCI

Other Cognitive Impairment in reference to the DSM IV-TR diagnostic criteria for Dementia of the Alzheimer’s Type. The four OCI are Aphasia, Apraxia, Agnosia and Disturbance in executive functioning

TCM

Traditional Chinese Medicine

VaD

Vascular Dementia

ZYDCD

Zhong Yao Da Ci Dian ‘Great Compendium of Chinese Medicines’

ZYFJDCD

Zhong Yi Fang Ji Da Ci Dian ‘Great Compendium of Chinese Medical Formulae’

Introduction

Natural products form the basis of systems of traditional medicine and they continue to be important in conventional medicine as sources for new drugs (Newman et al. 2003). Even when the methods of combinatorial chemistry are employed, natural products can provide biologically validated starting points and favourable lead structures for drug discovery (Breinbauer et al. 2002; Koehn and Carter 2005). Of the four anti-Alzheimer’s drugs approved in the period 1981–2002 that were new chemical entities, one was a natural product while the others were synthetic mimics of natural products (Newman et al. 2003). Approaches to finding new leads for drug development include high throughput screening of libraries of natural products, mining of database entries and the investigation of historical herbal texts (Buenz et al. 2004; Kong et al. 2009; Watkins et al. 2011). A review of approaches found that although the random collection of botanical specimens followed by high throughput screening remains the industrial approach of choice, the ethnobiological approach has been more successful since plant-derived drug discovery efforts began (Fabricant and Farnsworth 2001).

It is well-known that citations in classical Chinese herbal medicine (CHM) books led to the discovery of the anti-malarial artemisinin (Kong et al. 2008; Wright 2005). The CHM literature continues to receive research attention in attempts to translate traditional practices into modern use. Examples include the development of databases for cancer (Fang et al. 2005) and investigating historical treatments for Parkinson’s disease (Buenz et al. 2004, 2009). However, broadly applicable methodologies for systematically investigating the voluminous content of the traditional Chinese medical literature from the dynastic period still require development.

In developing a methodological approach to searching, screening and evaluating the traditional literature, the following needed to be considered: (1) selection of a suitable sample of the traditional literature, (2) identification of appropriate search terms, (3) establishment of approaches to extracting, verifying and storing data, and (4) development of an approach to evaluating, classifying and presenting data. With regard to each of these, the traditional literature presents particular challenges.

A feature of traditional CHM practice is that multi-herb formulae, comprising two or more herbs and hereafter referred to as ‘formulae’, are generally used in the clinical management of disorders. Therefore, formulae should be the primary focus of this investigation. However, the constituent herbs in a formula do not all target the principal symptom or disorder. From the traditional medicine perspective, herbs may have a number of roles within a formula with some targeting the primary disorder while others may aim to address the patient’s constitution, alleviate secondary symptoms, improve absorption or counter undesirable effects of other herbs (Bensky and Barolet 1990). Consequently, certain herbs are present in formulae intended for a diversity of conditions, examples include, Glycyrrhiza uralensis (gan cao) and Ziziphus jujuba (da zao). Such herbs could be expected to appear frequently in formulae regardless of the disorder for which it was intended. Also, individual herbs can be used to treat a wide range of symptoms and disorders. In some cases, the roles of the individual herbs may be discussed in the citation in the traditional literature but citations tend to be brief so such discussions are not frequent additions. Therefore, comprehensive pharmacopoeias, which describe the functions and indications of individual herbs, were consulted to determine which herbs in the formulae were considered specific for dementia and/or memory disorders.

There is overlap but no direct correspondence between the modern terms ‘dementia’, Alzheimer’s disease (AD), Mild Cognitive Impairment (MCI) or Age Associated Memory Impairment (AAMI) and the terms used in traditional Chinese medicine (TCM). In contemporary TCM clinical manuals lao nian chi dai ‘senile dementia’ and related terms usually encompass AD and vascular dementia (VaD) (Shi and Zhou 1997). The term lao ren jian wang ‘forgetfulness in the aged’ is broadly consistent with amnestic MCI or AAMI (Zhongjia Jizhu Jianduju 1996). The traditional term jian wang refers to ‘forgetfulness’, ‘poor memory’ or ‘impaired memory’ and is usually divided into a number of sub-types, some of which have little to do with age-related memory impairment (Wiseman 1996; Flaws and Lake 2003). In general, the terms used in TCM tend to be more general and encompass a number of modern medical categories. Moreover, in older traditional texts the number of terms is considerably greater and their scope of usage is less clearly defined. For example, the term chi dai which is now glossed as ‘dementia’ may refer broadly to ‘feeblemindedness’ or ‘unspecified mental retardation’ of various aetiologies (Lin 2002; Flaws and Lake 2003).

In the retrospective analysis of historical reports on the treatment of a disease, it cannot be assumed that a condition labelled as chi dai or jian wang referred to a condition that would now be considered AD, MCI or AAMI. Also, the extent to which it is possible to be confident that an instance of chi dai or jian wang in a traditional book was referring to a condition that would now be considered AD, VaD, MCI, AAMI or another disorder, is dependent upon the type and amount of information provided in the citation, and there is no plausible means of obtaining additional information. In this study, the approach taken was to develop a series of exclusion criteria and a scoring system to enable an assessment of the likelihood of a citation being an instance of AD or other age-related memory disorder.

For the purposes of this study the ‘traditional’ literature was limited to the dynastic period of Chinese history, so it included books written or published before or during 1911. This literature was selected since it forms the basis of modern TCM and is frequently referred to in modern textbooks and clinical manuals but these books are not typically found in on-line databases. The term ‘herb’ is used in a broad sense to include substances of plant, animal or mineral origin.

The first objective of this study was to develop a generic, systematic method for screening and evaluating citations from the traditional CHM literature that is clearly defined, replicable, and adaptable to a range of disorders. The method aimed to provide as its output a hierarchically ordered list of herbs and combinations of herbs than can be used to guide further experimental and/or clinical research. The second objective was to apply this methodology to investigate which CHMs were used to treat age-related memory disorders analogous to AD, MCI or AAMI. The third objective was to compare the herbs used most frequently for memory disorders in traditional formulae with the herbs listed for memory disorders in traditional pharmacopoeias. By identifying herbs that have been used in the clinical management of memory disorders over the span of the traditional CHM literature, this study aimed to provide lists of herbs and combinations of herbs that may warrant further experimental and/or clinical investigation to assess their value in the prevention or treatment of memory disorders.

Method

Sources of TCM literature

The extant traditional literature is not available as a single corpus or database but there are numerous published collections. Therefore the approach was to select from amongst the available collections, one that is searchable and contains a large sample of herbal formulae and their clinical applications. Of the collections examined, two potential sample collections were identified: Zhong Hua Yi Dian ‘Encyclopaedia of Traditional Chinese Medicine’, a CD of 1,000 full books, and Zhong Yi Fang Ji Da Ci Dian (ZYFJDCD) ‘Great Compendium of Chinese Medical Formulae’ which includes extracts derived from 685 books. The second of these was selected since it is the largest available collection of Chinese herbal formulae in print with 96,592 individual formula entries. It includes formulae derived from and referenced to at least 685 books which span about 2,000 years, with most deriving from the dynastic period (see Table 1). ZYFJDCD is readily available, well indexed and contains an index of the names of diseases and other disorders referenced to the individual formula entry (Peng 1994).
Table 1

Numbers of books in ZYFJDCD and formula citations in data sets by historical period

Historical perioda

Number of books in ZYFJDCD

Number of formula citations in full data set

Number of formula citations after exclusions

Number of formula citations at stage 7

Before Tang Dynasty (before 618)

7 (1%)

0

0

0

Tang and 5 Dynasties (618–960)

7 (1%)

13 (7.5%)

13 (8.7%)

2 (10.5%)

Song and Jin Dynasties (961–1271)

74 (10.8%)

55 (31.6%)

50 (33.6%)

3 (15.8%)

Yuan Dynasty (1272–1368)

28 (4.1%)

3 (1.7%)

3 (2.0%)

1 (5.3%)

Ming Dynasty (1369–1644)

143 (20.9%)

45 (25.9%)

44 (29.5%)

6 (31.6%)

Qing Dynasty (1645–1911)

353 (51.5%)

46 (26.4%)

39 (26.2%)

7 (36.8%)

Republic of China (1912–1949)

42 (6.1%)

0

0

0

Modern (1950 onwards)

31 (4.5%)

12 (6.9%)

0

0

Total

685

174

149

19

ZYFJDCD: Zhong Yi Fang Ji Da Ci Dian ‘Great Compendium of Chinese Medical Formulae’

aThe years of the historical periods have been adjusted to eliminate overlapping years

Zhong Yao Da Ci Dian (ZYDCD) ‘Great Compendium of Chinese Medicines’ was selected as the modern pharmacopoeia reference for the therapeutic indications of individual herbs. It contains 5,767 entries for individual herbs which are indexed to the names of the diseases or disorders for which they have been used (Jiangsu New Medical Academy 1986). The Ben Cao Gang Mu (BCGM) ‘Materia Medica Classified by Section and Sub-section’ was selected as the classical pharmacopoeia reference (Liu and Liu 2002). It was written c. 1578 and contains 1,892 monographs on individual herbs and remains an important source for modern Chinese pharmacopoeias (Lu 1966; Unschuld 1986; Needham et al. 1986; Zhen 1994). It also includes a list of 114 categories of disorders and the applicable herbs (Liu and Liu 2002).

In the selection of search terms, the approach taken was to consult dictionaries and medical nomenclatures (WHO 2007; Lin 2002; Wiseman 1996; Zhongjia Jizhu Jianduju 1996; Li et al. 2005) as well as the historical discussions in contemporary clinical manuals (Zhang 1992; Chen 1993; Gao 1995; Zhou and Gao 1995; Xu 1998; Li and Mei 1999; Zhang 2000a; Zhang 2000b; Li and Xie 2007; Flaws and Lake 2003; Shen 2006). Based on these, a list of search terms relevant to dementia and memory disorders and applicable to the traditional literature was compiled and adopted.

Development of data sets

For ZYFJDCD, data for all citations listed under the index terms that pertained to memory impairment and/or dementia were collated into spreadsheets. This formed the primary data set. For each herbal formula, the following information was collated: index term, formula name; the name of each individual herb that constituted the formula; the disorders, signs and symptoms for which the formula was intended; the name of the book from which the formula was derived; the year in which the book was written. The year was based on the list of books in ZYFJDCD volume 11 but in cases where the year was unclear, other sources were consulted (Zhen 1994; Jia 1982; Yu and Fu 1992). When no year was specified, it was imputed as the year of the author’s death or the last year of the historical period (dynasty etc.).

The data derived from ZYDCD and BCGM comprised secondary data sets which aimed to identify which herbs within the formulae were specific for memory impairment and/or dementia. For ZYDCD and BCGM the following information was collated for each herb: index term, name of herb, botanical or other scientific name(s).

Data classification procedures

Established systems for the clinical diagnosis of AD, MCI and AAMI were examined to determine which could be adapted for scoring citations (American Psychiatric Association 2000; Crook et al. 1986; Petersen 2004; Winblad et al. 2004; Dubois et al. 2007; McKhann et al. 1984). The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM IV-TR) criteria for the clinical diagnosis of probable dementia of the Alzheimer’s type (Zhang 2000a; Bao 2003; American Psychiatric Association 2000) were selected as the basis for developing the inclusion and exclusion criteria and the scoring of citations as possible AD, since this system relies primarily on clinical observation rather than investigative tests. Secondary to this, Petersen’s criteria for amnestic MCI (Petersen 2004; Winblad et al. 2004) and the criteria for AAMI reported by Crook et al. (1986) were adapted for classifying entries that did not meet the criteria for probable AD.

Each herbal formula from ZYFJDCD was classified according to a system that was primarily based on the DSM IV-TR criteria (in English and Chinese) for the clinical diagnosis of probable dementia of the Alzheimer’s type (Zhang 2000a; Bao 2003; American Psychiatric Association 2000; Shen 2006). The system of classification aimed to identify formulae that were intended for conditions more or less similar to AD and comprised four main components as below. Ranking scores (ranging from 0 to 2) were allocated for the memory impairment and ageing components to differentiate sub-groups according the specificity of the information in the citation.
  1. (1)

    Exclusions: When a formula was intended for disorders of children; disorders associated with childbirth; acute disorders; mental or physical disorders dissimilar to senile dementia; possible stroke; or was derived from a book written or published after 1911, it was excluded. Editions published after 1911 of material written in or before 1911 were included.

     
  2. (2)

    Memory impairment: When the only information was a term corresponding to or synonymous with the Chinese term jian wang (forgetfulness, memory impairment), a ranking score of 1 was allocated. When the formula was intended for memory impairment in old people, or the description was detailed enough to suggest a disorder of episodic memory consistent with AD or MCI, a ranking score of 2 was allocated. Formulae intended for memory improvement or for assisting study which did not mention a memory disorder received a score of 0 and were excluded.

     
  3. (3)

    Ageing: When the formula was explicitly stated as intended for aged people, it was scored 2. When ageing could be inferred from the context it was scored 1, for example, when the formula name indicated it was intended for promoting longevity; the functions and applications indicated the formula was for treating disorders of ageing or to regain youthfulness; or the book title indicated its content was intended for older people or for longevity.

     
  4. (4)

    Four other groups of cognitive impairment (OCI): When the formula was intended for any of the following signs and symptoms specified in DSM IV-TR, a score of 1 was allocated for each—Aphasia (language disturbance); Apraxia (impaired ability to carry out motor activities despite intact motor function); Agnosia (failure to recognise or identify objects despite intact sensory function); and/or Disturbance in executive functioning (i.e. planning, organizing, sequencing, abstracting) (American Psychiatric Association 2000).

     

These four components were combined and organised into a hierarchical structure with citations satisfying all criteria at the highest level being considered more likely to have referred to instances of AD than those that were lower in the hierarchy as follows.

When there were no exclusions, both memory impairment and ageing received rankings of 2 and there was at least one OCI, a citation was considered to have the highest level of likelihood as an instance of AD. When the rankings were lower (i.e. 2 & 1 or 1 &1), the citation was still considered a possible instance of AD, with the level of likelihood being considered lowest when memory and ageing were ranked as 1.

When both memory impairment and ageing received rankings of 2, but there were no scores for the OCIs, amnestic MCI was considered likely (Petersen 2004; Shen 2006). When ageing was ranked 2 or 1 and memory impairment received a ranking of 1, either amnestic MCI or AAMI were considered possibilities (Crook et al. 1986; Petersen 2004).

Numerical codes were allocated for each of the individual herbs in each formula. When a herb was listed under multiple Chinese names, but these referred to the same herb, the same code number was used. Unique code numbers were allocated for different parts of the same plant when these are considered distinct medicines in CHM, otherwise the same code number was used. ZYDCD was used as the standard reference for resolving issues of herbal nomenclature and identity. Data entered into the spreadsheets were checked against copies of the ZYFJDCD, ZYDCD and BCGM by an investigator. Data from ZYFJDCD were scored independently by two native speakers of Chinese. A log of decisions was kept and consensus reached by discussion between the two scorers and an investigator.

Statistical analysis

Analyses of the ZYFJDCD data were conducted in PASW Statistics Version 18 (SPSS Inc 2009). All the numerical data for each formula and each herb in each formula were entered into PASW and independently checked. Formulae that received scores for any of the exclusion criteria were removed from the analyses. The remaining data were classified according the scores received for Memory impairment (M), Ageing (A) and the four OCIs. The frequencies of the formulae and herbs that satisfied each of these criteria, singly and in combination, were tabulated. Hierarchical cluster analysis (squared Euclidian distance, between groups) was used to further explore the combinations of herbs that appeared repeatedly in the formulae intended for both memory impairment and ageing.

Results and discussion

Search terms and search results

The ZYFJDCD index lists 16 references under the index term chi dai ‘dementia’ and 149 under jian wang ‘forgetfulness’. More than one formula was listed under some of these references, so the full data set comprised 174 formulae (16 for chi dai, 158 for jian wang) which were derived from 75 different books. The earliest book was Bei Ji Qian Jin Yao Fang (c. 650 AD) by Sun Si-Miao, the most recent book was published in 1985. The frequency of formula citations by historical period is presented in Table 1.

Formulae were excluded according to the criteria as follows: deriving from post 1911 books (n = 12); disorders of children (n = 2); associated with childbirth (n = 0); acute conditions (n = 4); symptoms consistent with stroke (n = 2); or disorders unlike dementia (n = 8). Following these exclusions, the ZYFJDCD data set comprised 149 formulae derived from books written over the period c. 650 to 1911 (see Table 1). These formulae were composed of 1,403 herbs so the average number of herbs per formula was 9.4. The composition of each formula was different even though some formulae had the same or similar names. In traditional CHM it is not unusual for formulae with the same name to vary in their ingredients and also for the same set of ingredients to have multiple names. Since no duplicate formulae were found, it appears that the ZYFJDCD editors had used formula composition, rather than name alone, as the criterion for inclusion in the compendium.

Six of the 149 formulae were indexed in ZYFJDCD under chi dai and 143 were under jian wang but these exact terms were not necessarily used. The term chi dai was used in one citation, three used the term dai bing and three (one of which was indexed under jian wang) were intended for disorders described as ‘like’ or ‘resembling’ dementia (ru chi). Jian wang was the most common term overall (n = 85) but synonymous terms, such as duo wang (n = 14), xi wang (n = 12), hao wang (n = 8), shan wang (n = 4) and others (n = 4) were also used. In addition, 13 formulae indexed under jian wang were intended for memory improvement or assisting study only.

Classification and ranking of formula citations

The scores for the three classification criteria relating to the diagnosis of probable dementia are reported in Table 2. Twenty-two formulae made no mention of memory. These were either intended for chi dai and associated disorders and made no mention of memory impairment or were indexed as jian wang but were intended for improving memory, assisting study or for disorders due to excessive study. The majority of formulae (116) were intended for memory impairment (i.e. jian wang or associated terms) alone or in association with other symptoms but provided no further detail on the nature of the memory impairment. Only 11 provided a description of memory impairment consistent with dementia.
Table 2

Number of included formulae and herbs according to classification criteria for dementia showing scores for memory, ageing and four other cognitive impairments (OCI)

Ranking score

Description

Number of formulae

Number of herbs

1. Memory-score

 0

No mention of memory impairment

22 (14.8%)

226 (16.1%)

 1

Memory impairment (no further detail)

116 (77.9%)

1086 (77.4%)

 2

Memory disorder consistent with dementia

11 (7.4%)

91 (6.5%)

2. Ageing-score

 0

No mention of ageing or longevity

128 (85.9%)

1192 (85.0%)

 1

Indirect mention of ageing/longevity

15 (10.1%)

154 (11.0%)

 2

Indicated for older people

6 (4.0%)

57 (4.1%)

3. Other cognitive impairment (OCI)

Aphasia

5 (3.4%)

49 (3.5%)

 

Apraxia

0

0

 

Agnosia

0

0

 

Disturbance in executive functioning

0

0

 

Total entries

149

1403

Exclusions: post 1911 books, disorders of children or associated with childbirth, acute conditions, symptoms consistent with stroke, disorders unlike dementia

References to the elderly or to the promotion of longevity were infrequent overall. Only 15 formulae made indirect references to ageing, and only six formulae were explicitly indicated for older people. Five formulae mentioned a condition that may have been a form of aphasia. A few formulae had received scores for agnosia but these were removed at an earlier stage by the exclusion criteria.

The included data were subsequently organised into a hierarchical structure with levels of decreasing strength of assemblage of the three groups of criteria for dementia (Table 3). There were no formulae associated with levels 1 or 2 i.e. memory (ranked 2) plus ageing (ranked 1 or 2) plus any OCI. One formula was identified when all three criteria were combined at the lowest level of ranking i.e. memory (ranked 1 or 2) plus ageing (ranked 1 or 2) plus any OCI. This formula was named Shou xing wan or ‘God of longevity pill’ and contained 15 different herbs. Shou xing wan was indexed as chi dai and was intended for ‘phlegm clouding the senses, speaks as if demented, and frequent forgetfulness (duo wang)’ (Peng 1994). From a modern perspective, the condition for which this formula was intended had the symptoms of mental dullness, impaired or confused speech and memory impairment but the nature of the memory impairment was not explained. Also, its use for older people is inferred from the formula name. While the indications for this formula are suggestive of AD, it lacks specificity in its description of symptoms.
Table 3

Summary of hierarchical analysis of combined criteria showing decreasing specificity for dementia with increasing level: frequency of formulae, number of herbs and distinct herbs, and year(s) of citation

Level

Inclusion criteria

Formulae

Herbsa

Distinct herbsa

Citation year(s)

1

M = 2 + A = 2 + any OCI

0

0

0

 

2

M = 2 + A = 2 or 1 + any OCI

0

0

0

 

3

M = 2 or 1 + A = 2 or 1 + any OCI

1

15

15

1773

4

M = 2 + A = 2

4

36

19

1687, 1839

5

M = 2 + A = 2 or 1

4

36

19

1687, 1839

6

M = 1 + A = 2 or 1

15

140

50

c.650–c.1911

7

M = 2 or 1 + A = 2 or 1

19

176

53

c.650–c.1911

M memory score, A ageing score, OCI four other cognitive impairments

aHerbs refers to the number of herbs that comprise the formulae. Distinct herbs refers to the number of different herbs represented

Mention of the OCIs was generally infrequent so the subsequent three levels combine memory plus ageing at rankings of 1 or 2 (Table 3). At level 4 (memory = 2 plus ageing = 2), four formulae comprising 19 different herbs were identified. These did not include Shou xing wan. Two formulae were indicated simply for memory loss in old age but the other two provided more detail on the nature of the memory impairment and were translated as follows:

Sheng hui tang: ‘the person can’t remember recent events and when someone tells them about the earlier event, it is as if they had no knowledge of it’ (Peng 1994).

Qiang ji tang: ‘due to old age the Kidney Water becomes empty and the Heart Blood becomes dry, this leads to frequently forgetting recent events; even though someone tells them what happened previously, it is as if they had no knowledge of it’ (Peng 1994).

In both of these examples, the impairments of episodic memory described are consistent with amnestic MCI or AD and are clearly not the kind of forgetfulness associated with normal ageing. In the second example, an explanation for the disorder is provided in terms of traditional theory, which suggests the doctor was familiar with this type of disorder. However, three of the four formulae were derived from the same book (Bian Zheng Lu, 1687), so this is a narrow sample.

At level 6 (memory = 1 plus ageing = 2 or 1), 15 formulae were represented. This sample spanned the whole period of the data set (c. 650–1911) and included Shou xing wan from level 3. These formulae were intended for conditions that at least satisfied the criteria for an instance of possible AAMI but none provided details on the nature of the ‘forgetfulness’.

At level 7 (memory = 2 or 1 plus ageing = 2 or 1), 19 formulae were represented including all those identified at previous levels. There were a total of 176 herbs in these formulae (average of 9.3 herbs per formula) and 53 different herbs were represented. Since the formulae in this group were all intended for age-related memory impairment broadly consistent with AAMI, amnestic MCI or AD, further investigation of their constituent herbs was undertaken (see below).

Despite the similarity between the modern term for senile dementia lao nian chi dai ‘dementia in the elderly’ and the ZYFJDCD index term chi dai ‘dementia’, based on the criteria used in this study only one of the formulae indexed under chi dai was intended for a disorder broadly consistent with AD. A number of formulae that were indexed under jian wang ‘forgetfulness’ were for memory impairments consistent with AD or amnestic MCI but the traditional literature tends to be terse, with symptoms and signs being named without any detailed description or information regarding severity. This limits the inferences that can be made. It is probable that when ‘forgetfulness’ was mentioned, it referred to ‘forgetfulness’ that was abnormal or sufficiently remarkable to be of concern and to require medical attention. So it is likely that at least some of the additional citations identified at level 6 would have referred to conditions considerably more severe than AAMI but we lack any means of distinguishing these. Therefore the evidence is insufficient to conclude that AD was present in China during the dynastic period. Nevertheless, conditions consistent with AAMI and/or amnestic MCI were treated throughout the full span of the included literature (c.650–c.1911) and descriptions of profound impairments of episodic memory consistent with AD or MCI can be found.

Frequency of herbs

The identities and frequencies of each of the different herbs associated with level 3 (15 different herbs) and level 4 (19 different herbs), together with the frequencies of these herbs at levels 6 and 7 are summarised in Table 4. The herbs are listed in descending order according to their frequency at level 7 but herbs that only appear once at levels 6 and 7 are not included in the table unless they are also included at levels 3 or 4.
Table 4

Distinct herbs in all formulae satisfying the criteria for hierarchy levels 3, 4, 6 and 7 as defined in Table 3

Scientific name(s)

Chinese name(s)

Frequency at level 3

Frequency at level 4

Frequency at level 6

Frequency at level 7

Polygala tenuifolia Willd., P. sibirica L

aYuan zhib

1

3

13

16

Rehmannia glutinosa Libosch

Di huangb

1

4

9

13

Poria cocos (Schw.) Wolf

aFu lingb

1

1

11

12

Panax ginseng C.A. Mey

Ren shenb

1

3

8

11

Acorus gramineus Soland., A. tatarinowii Schott., A. calamus L., or possibly Anemone altaica Fisch

aChang pub

0

3

8

11

Ophiopogon japonicus (Thunb.) Ker-Gawl., O. bodinieri or Liriope spp.

Mai dongb

0

3

5

8

Ziziphus spinosa Hu., Z. mauritiana

Suan zao renb

0

3

5

8

Angelica sinensis (Oliv.) Diels

Dang guib

1

1

6

7

Poria cocos (Schw.) Wolf. (with pine root inclusions)

aFu shenb

0

2

5

7

Glycyrrhiza uralensis Fisch

aGan caob

1

1

5

6

Atractylodes macrocephala Koidz

Bai zhu

1

1

4

5

Cinnabar (mercuric sulfide)

aZhu shab

1

1

4

5

Cinnamomum cassia Presl. or other Cinnamomum. spp.

Rou gui/Gui zhi

1

0

4

4

Citrus reticulata Blanco., C. tangerina Hort.et Tanaka

Chen pi

1

0

4

4

Asparagus cochinchinensis (Lour.) Merr

Tian dong

0

1

3

4

Biota orientalis L., Platycladus orientalis (L.) Franco

aBai zi renb

0

2

2

4

Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao

Huang qi

1

1

2

3

Paeonia lactiflora Pall

Bai shao

1

0

3

3

Schisandra chinensis (Turcz.) Baill., or other Schisandra spp

Wu wei zi

1

0

3

3

Cornus officinalis Sieb. & Zucc.

Shan zhu yu

0

2

0

2

Fossilized bones/teeth

aLong gu/chib

0

1

1

2

Sinapsis alba L

Bai jie zi

0

2

0

2

Saposhnikovia divaricata (Turcz.) Schischk

Fang feng

0

0

2

2

Lycium chinense Mill., L. barbarum L

aDi gu pi

0

0

2

2

Aucklandia lappa Decne

Mu xiang

0

0

2

2

Dimocarpus longan (Lour.) Steud

aLong yan rou

0

0

2

2

Citrus aurantium L

Zhi shi

0

0

2

2

Arisaema heterophyllum Bl. or other A. spp

Dan nan xing

1

0

1

1

Amber

aHu po

1

0

1

1

Scrophularia ningpoensis Hemsl

aXuan shenb

0

1

0

1

Total herbs at Level

 

15

36

140

176

aIndexed for jian wang ‘forgetfulness’ in the modern pharmacopoeia Zhong Yao Da Ci Dian (ZYDCD)

bIndexed for jian wang in the Ming dynasty pharmacopoeia Ben Cao Gang Mu (BCGM)

Notes. 1. the results for hierarchy Level 5 are not shown since they are the same as for Level 4; 2. Level 6 includes the single formula at Level 3; 3. Level 7 includes all previous levels; 4. all herbs are included for Levels 3 and 4; 5. all herbs of a frequency of 2 or above are included for Levels 6 and 7

The top four herbs are represented at all four levels and all of the top ten herbs appear at three or more levels. So there was general consistency in the herbs used frequently in the formulae at each level. Nevertheless, there was also considerable diversity in the low frequency herbs with 26 only appearing once at level 7.

Since the citations did not indicate which herbs were specific for the memory disorder and which had been included in the formulae for other reasons, this information could only be inferred by reference to pharmacopoeias which list the actions and indications of specific herbs.

In ZYDCD, 30 different herbs were indexed under the term jian wang. Within these references, jian wang was the most commonly used term (n = 26) followed by shan wang (n = 4), xi wang (n = 3), duo wang (n = 2), hao wang (n = 2) and others (n = 2). None of the references provided a detailed description of the nature of the memory disorder and none was for improving memory only. Chi dai ‘dementia’ was not an index term in ZYDCD. Since it appeared possible that chi dai may have been included under the index term dian kuang ‘psychosis’ (63 entries), these references were searched for relevance to chi dai. A single reference containing the term chi was found but it was unrelated to dementia whereas an additional herb for duo wang was located (i.e. zhu sha cinnabar). This was added, so 31 herbs were identified for ‘forgetfulness’ based on the two ZYDCD index terms. In BCGM the only relevant index term was jian wang and 39 different herbs were listed (Liu and Liu 2002). The data sets derived from these pharmacopoeias were cross-referenced to the results in Table 4.

Of the 31 herbs identified in the ZYDCD indices, 17 were present in the formulae at level 7 and 12 of these are marked in Table 4. Of the 39 different herbs listed for jian wang in BCGM, 18 are present in formulae at level 7 and 14 of these are marked in Table 4 (Liu and Liu 2002). Overall, 22 of the 53 different herbs (41.5%) and all of the ten highest frequency herbs in the formulae identified at level 7 were also indicated individually for memory disorders in one or both of the pharmacopoeias. Although the final list of formulae at level 7 were considered as indicated for disorders broadly consistent with AAMI, within the list of constituent herbs (Table 4), the top ten were all present at Level 4 which is broadly consistent with amnestic MCI.

Botanical identity of herbs

Since the ZYFJDCD data were derived from traditional books, the scientific identity of a herb can only be inferred based upon the Chinese names, which may refer to more than one species. For example, the herb yuan zhi is derived from Polygala tenuifolia or the related species P. sibirica (Bensky et al. 2004; Jiangsu New Medical Academy 1986). In the case of Rehmannia glutinosa, its root is typically prepared into two forms, a steamed and dried form called shu di huang and an uncooked dried form called sheng di huang which are considered separate herbs in CHM (Bensky et al. 2004; Jiangsu New Medical Academy 1986). However, in older formulae the form of di huang may not be specified. Since all forms derive from the same part of the same plant, these have all been combined under the term di huang. Had these three names been separated, the frequencies of each form of di huang would have been lower. For the herb chang pu, the most commonly used species are Acorus gramineus and A. tatarinowii, which are both now specified as shi chang pu, but in some formulae the herb is only specified as chang pu, so it is possible that A. calamus (now called bai chang pu or shui chang pu) was intended (Bensky et al. 2004; Jiangsu New Medical Academy 1986). Also, Anemone altaica, which is now called jiu jie chang pu, may have been included within the scope of the term chang pu (Bensky et al. 2004). Similarly, mai dong usually refers to Ophiopogon japonicus but various Liriope species may also be used as this herb (Bensky et al. 2004; Chen 1997; Jiangsu New Medical Academy 1986). In Table 4, we have provided separate entries for fu ling and fu shen which derive from separate parts of the same plant. Fu ling is the sclerotium of the of the fungus Poria cocos whereas fu shen is composed of Poria cocos as well as parts of the roots of the trees upon which it grows. These root inclusions could come from a number of pine species including Pinus massoniana (ma wei song) and Pinus densiflora (chi song) (Jiangsu New Medical Academy 1986). Consequently, fu ling and fu shen have different compositions and are therefore considered as distinct herbs. When conducting further research into these and other herbs, issues of identity need to be considered and we suggest that a number of species and forms should be included in assays, not just the one that is most commonly listed in modern books.

Clustering of herbs

Although Table 4 provides an indication of which herbs were most commonly used at level 7, all of the 53 different herbs were actually used in 19 different combinations (i.e. formulae). To determine which combinations of herbs were used, hierarchical cluster analysis was undertaken of the 27 herbs with total frequencies greater than 1. The resultant dendrogram (Fig. 1) shows that most of the highest frequency herbs are in a cluster of 4 herbs: chang pu, fu ling, yuan zhi and ren shen with the closest linkage being between the last three. The remainder of the herbs are in the second, more complex cluster. The second most frequent herb di huang is in a sub-cluster of the second cluster together with mai men dong, suan zao ren and dang gui. Fu shen and gan cao form another sub-cluster. These three clusters include the ten most frequent herbs, all of which are indicated for memory impairment. Moreover, all 13 of the herbs from bai zi ren to chang pu are indicated for memory impairment (see Fig. 1). Therefore the most common constituent herbs of the formulae included at level 7 were not only each indicated for memory impairment, these herbs tended to cluster together. This finding validates the approach taken in this study.
Fig. 1

Dendrogram of hierarchical clustering of all herbs at Level 7 with frequencies greater than one using Squared Euclidian Distance (between groups). Herb names are in pin yin romanisation. The higher frequency herbs cluster towards the lower end of the X axis. For the botanical identities of the higher frequency herbs see Table 4

Considerations when interpreting results

The exclusion criteria were effective in removing formulae for conditions that were unlikely to have been instances of AD, MCI or AAMI but there were limitations in the use of the adapted DSM IV-TR criteria, in terms of their capacity to identify possible AD versus MCI. It is noteworthy that only a small number of formulae received scores for any of the four OCIs and only one could satisfy all four groups of criteria for possible AD. Also, so few formulae satisfied the criteria for possible amnestic MCI that the analyses of herb frequency were, of necessity, based on the formulae included at a lower level of specificity (i.e. level 7) which does not distinguish between these categories of age-related memory disorders.

In the case of the modern pharmacopoeia ZYDCD, the indexing to disorder/symptom was found not to be comprehensive in the case of jian wang. Similarly, the list in BCGM appears not to have been comprehensive. Therefore, even when these two books were used together, they may not have identified all the herbs in Table 4 that were indicated individually for memory disorders. In future studies we suggest that rather than using the index terms in these pharmacopoeias, shortlisted herbs should be compared against their full entries in a comprehensive pharmacopoeia such as ZYDCD or Zhong Hua Ben Cao (State Administration of Traditional Chinese Medicine ‘Chinese Materia Medica Committee’ 1999).

Although the frequency of inclusion of a specific herb in herbal formulae in the traditional Chinese literature cannot be interpreted as evidence of efficacy, it does provide an indication of the relative degree of traditional usage for the particular disorder. Also, it should be noted that the herbs listed in pharmacopoeias for memory impairment tend to be used for multiple disorders, of which memory impairment is one.

The approach taken here provides a rational method for using the traditional literature to identify and short-list herbs and combinations of herbs with potential value for further evaluation as therapeutic candidates.

Conclusions

Using the method presented in this study it is evident that treatments using multi-herb formulae for age-related memory disorders whose descriptions are consistent with AAMI, amnestic MCI or more severe disorders have been recorded throughout the traditional Chinese literature since at least the fifth century. On average, these formulas contained about nine different herbs. The herbs most frequently included were also individually indicated for memory disorders and were used in specific combinations. These herbs may warrant further experimental and clinical evaluation, both individually and in combination, to explore their potential for the development of agents for the prevention and/or treatment of age-related memory disorders.

Notes

Acknowledgments

We thank the Preventive Health National Flagship Program, Commonwealth Scientific and Industrial Research Organization (CSIRO) for providing partial funding support. The project is also partially supported by an International Grant from the Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Province, China. We thank Ms Chang Su-Yueh, Mr David Lu, Dr Iris Zhou and Dr Sheng Shu-Jun for their work in data extraction, compilation and scoring, Dr Tony Zhang, Dr Angela Yang and Prof Eddie Pang for comments. We also wish to thank the library staff at Hong Kong Baptist University and at the Guangzhou University of Chinese Medicine for their kind assistance with the literature search process.

Conflict of interest

The authors declare that they have no conflict of interest

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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Brian H. May
    • 1
  • Chuanjian Lu
    • 2
  • Louise Bennett
    • 3
  • Helmut M. Hügel
    • 4
  • Charlie C. L. Xue
    • 1
    • 2
  1. 1.Traditional and Complementary Medicine Research Program, Health Innovations Research Institute; WHO Collaborating Centre for Traditional Medicine, School of Health SciencesRMIT UniversityBundooraAustralia
  2. 2.Guangdong Provincial Academy of Chinese Medical SciencesGuangzhouChina
  3. 3.Pre-clinical and Clinical Health SubstantiationCSIRO Food and Nutritional SciencesWerribeeAustralia
  4. 4.School of Applied Sciences [Applied Chemistry]RMIT UniversityMelbourneAustralia

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