A Systematic Review on Natural Medicines for the Prevention and Treatment of Alzheimer's Disease...

8/11/2019 A Systematic Review on Natural Medicines for the Prevention and Treatment of Alzheimer's Disease With Meta-An

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A Systematic Review on Natural Medicines forthe Prevention and Treatment of Alzheimer s

Disease with Meta-Analyses of InterventionEffect of Ginkgo

Mengmeng Yang, * ,a Dan Dan Xu, * ,a Yan Zhang, * Xinyou Liu, *

Robin Hoeven and William Chi Shing Cho

* Department of Pharmacy , Tangdu Hospital The Fourth Military Medical University , Xi an , China

Faculty of Life Sciences , University of Manchester Manchester , United Kingdom

Department of Clinical Oncology , Queen Elizabeth Hospital Hong Kong SAR

Abstract: We performed a systematic review to evaluate the ef cacy of natural medicines for the treatment of Alzheimer s disease (AD) in randomized controlled trials (RCTs). Disease-speci c and intervention terms were searched in MEDLINE, EMBASE, the Cochrane Li-brary and PsycINFO to identify RCTs for the AD intervention of natural medicines, andsearched for literatures in English language. The RCTs compared natural medicines andeither placebo or orthodox medication in AD patients. The quality of literature was evaluatedby Jadad s score and the Cochrane assessing tool to reduce the risk of bias. Meta-analysisand the heterogeneity of results across the trials were performed. Out of the literatures, 21clinical reports were included in this review that satis ed the particular selection criteria.Apart from Ginkgo, other treatments we came across had minimal bene ts and/or the

methodological quality of the available trials was poor. The meta-analyses showed that Ginkgo had better outcomes than the placebo, with the standardized mean difference (SMD)between Ginkgo and the placebo on cognition being 1.62 (95% CI: 2.69 to 0.56) andon activities of daily living being 1.55 (95% CI: 2.55 to 0.55), with the existenceof signi cant heterogeneity across studies. The meta-analysis for assessing the preventioneffect of Ginkgo against AD suggested that risk ratio (RR) is 1.06 (95% CI: 0.92 to 1.22)between Gingko and the placebo, with no signi cant heterogeneity across studies (test for

Correspondence to: Dr. William Chi Shing Cho, Department of Clinical Oncology, Queen Elizabeth Hospital, 30Gascoigne Road, Kowloon, Hong Kong SAR. Tel: ( 852) 2958-5441, Fax: ( 852) 2958-5455, E-mail:[email protected] or Dr. Mengmeng Yang, Clinical Pharmacy Services, Department of Pharmacy,

Tangdu Hospital of the Fourth Military Medical University, 569 Xinsi Road, Xi

an, China. Tel: ( 86) 29-8477-7547, Fax: ( 86) 29-8477-7154, E-mail: myang [email protected] a These authors contributed equally to this work.

The American Journal of Chinese Medicine, Vol. 42, No. 3, 505 521 2014 World Scienti c Publishing Company

Institute for Advanced Research in Asian Science and MedicineDOI: 10.1142/S0192415X14500335

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o n 0 6 / 0 6 / 1 4 . F o r p e r s o n a l u s e o n l y .
http://dx.doi.org/10.1142/S0192415X14500335http://dx.doi.org/10.1142/S0192415X14500335


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heterogeneity, p 0 :49 ). Our results suggest that Ginkgo may help established AD patientswith cognitive symptoms but cannot prevent the neurodegenerative progression of the

disease.

Keywords : Alzheimer s Disease; Ginkgo; Meta-Analysis; Natural Medicines; SystematicReview.

Introduction

Alzheimer s disease (AD) is the most common form of dementia, and is de ned as a progressive neurodegenerative disease characterized by cognitive deterioration together

with behavioral disturbances and declining activities. It is hypothesized that AD is causedby the reduced level of the neurotransmitter acetylcholine, the deposition of beta-amyloid,or tau protein abnormality in the brain. Nowadays the available therapeutic medicationsmainly include cholinesterase inhibitors (tacrine, rivastigmine, galantamine, or donepezil),NMDA receptor antagonist (memantine), anti-in ammatory drugs (NSAIDs), nootropicagent (piracetam) and a variety of antioxidants (vitamins) ( Selkoe , 2001 ). However, thesuccess of these treatment strategies cannot be predicted and often offer very limitedbene ts in clinic.

Due to the limitation of pharmacological interventions, the therapies from natural originprovide alternative and complementary choices for patients with AD ( Perry et al. , 1999 ). In

this review, we carried out a systematic analysis of randomized controlled trials (RCTs), toassess the ef cacy of natural medicines vs. placebo or active control in the prevention or treatment for AD. This review aims to provide a comprehensive assessment on the inter-vention of natural medicines in clearly speci ed AD or dementia of AD type. The non-Alzheimer types of dementia, including vascular dementia, dementia with Lewy body,mixed dementia and Parkinson s disease, were excluded. Natural medicines included inthis review comprise original or extracted forms of naturally occurring medicines. Thequality of RCTs was assessed with Jadad s score, followed by Cochrane Collaboration s Risk of bias tool. The summary intervention effect estimate is calculated as a weightedaverage of the intervention effects estimated in the individual studies by means of random-effects meta-analysis, which give us a deeper insight in the ef cacy of natural medicinesfor AD.

Methods

Search Strategy

Disease-speci c terms ( Alzheimer disease or dementia ) combined with interventionterms ( phytotherapy or phytomedicine or natural product or natural medicine or herb ) were searched in MEDLINE from 1950 to July 2013, EMBASE from 1980 to July2013, the Cochrane Library from 1990 to July 2013 and PsycINFO from 1990 to July 2013to identify RCTs for AD intervention of natural medicines in the English language.

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Inclusion Criteria

Types of Studies

All published, double-blinded, randomized, placebo-controlled trials examining ef cacy of natural medicines in patients with AD were included.

Types of Participants

Diagnostic criteria included Diagnostic and Statistical Manual of Mental Disorders (DSM),National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer sDisease and Related Disorders Association (NINCDS ADRDA).

Types of Interventions

Comparisons of natural medicines and either placebo or orthodox medication were per-formed.

Types of Outcome Measures

(1) Cognition: Mini-Mental State Examination (MMSE), Cognitive subscale of the Alz-heimer s Disease Assessment Scale (ADAS-Cog), or Syndrom-Kurz test (SKT); (2) Ac-tivities of daily living (ADL): The AD Activities of Daily Living International Scale (ADL-IS), Gottfries-Brne-Steen-Activities of Daily Living (GBS-ADL) scale, Geriatric Evalu-ation by Relative s Rating Instrument (GERRI), or Nrnberger Alters-Beobachtungsskala

(NAB); (3) Global impression: Alzheimer

s Disease Cooperative Study Clinical GlobalImpression of Change (ADCS-CGIC), Clinical Dementia Rating Scale (CDR), ClinicalGlobal Impression (CGI), or Gottfries-Brne-Steen (GBS); (4) Behavior/Neuropsychology:The Neuropsychiatric Inventory (NPI) or Hamilton Rating Scale for Depression (HRSD);(5) Quality of life: Alzheimer Disease Related Quality of Life (ADRQL); (6) Communi-cation/Social Interaction: Verbal Fluency Test (VFT).

Data Collection and Analysis

Two authors (MY, DDX) were independently involved in database searching, reference

screening and inclusion assessment. Any discrepancies were resolved by consensus withthe other authors (YZ, XL, RH, WCC). One author (MY) performed data extraction andconstructed a worksheet including authors and publication year, country, duration, samplesize, trial type, age of the participants, diagnostic system, outcome measures, and details of intervention for each study. Another author (DDX) veri ed the extracted data. Since de-mentia was reported as several different types, the studies were included with either reported AD cases only or presented sub-group analyses for AD patients.

Selection of Studies with Jadad s Scores

The quality of the studies was assessed using Jadad s scores by two authors (MY, DDX)(Jadad et al. , 1996 ) and nally con rmed by another author (WCC). Scores were assigned

META-ANALYSES OF GINKGO ON ALZHEIMER S DISEASE 507

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if the trial was described as randomized (1 point), double-blind (1 point) or had with-drawals/dropouts (1 point). The additional points could be awarded (1 extra point in eachcase) if the method of randomization or double blinding was appropriate. Conversely,points could be deducted (1 point in each case) if the study was described as randomized or double blind, but the methods were inappropriate. The trials with Jadad s scores 3 wereincluded in this review.

Assessment of Risk of Bias in Included Studies

Trials with Jadad s scores 3 were subjected to Cochrane Collaboration s tool for assessing the risk of bias. The assessment domains include selection bias (random sequence

generation; allocation concealment), performance bias (blinding of participants and per-sonnel; blinding of outcome; incomplete outcome data), reporting bias (selective report-ing), and other bias (other sources of bias).

Assessment of Heterogeneity and Data Synthesis

All statistics were conducted with Review Manager (RevMan) version 5.2 (Copenhagen:The Nordic Cochrane Centre, the Cochrane Collaboration, 2012). For a speci c outcome,the heterogeneity of results across the trials, which was analyzed by the intention-to-treat (ITT) approach, was evaluated. A xed-effects model, without weighting of the studies,

was used when there was a lack of signi cant heterogeneity ( p > 0 :10 . If signi cant heterogeneity was observed ( p 0 :10 ), a random effects model, which assigns a weight toeach study based on individual study variance as well as between study variance, was usedto pool the results together. The standardized mean difference (SMD) for the same outcomeis used as a summary statistic in meta-analysis and presented in a forest plot. The likelihoodof publication bias was assessed in the context of visual inspection of funnel plots.

Results

Description of the Included Studies

Study ow diagram in Fig. 1 illustrates the result of the search and the process of screeningand selecting studies for inclusion in the review. 1228 records were retrieved by theelectronic searches, of which 704 were duplicates and 491 were excluded according toinclusion criteria in the Methods for general relevance. 35 full-text articles with Jadadscores 3 were considered as potentially eligible after screening. 14 studies were further excluded without explicit presentation for dementia of the AD type. The remaining 21studies were included in this review, of which 8 were the interventions of Salvia of cinalis(Akhondzadeh et al. , 2003a ), Melissa of ninalis (Akhondzadeh et al. , 2003b ), Crocussativus (Akhondzadeh et al. , 2010 ), curcumin ( Baum et al. , 2008 ), huperzine A ( Ra iet al. , 2011 ; Xu et al. , 1999 ) and Fuzhisan ( Bi et al. , 2011 ). A Characteristics of IncludedStudies table (Table 1) comprises a succinct summary of the trials information, including

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T a b l e 1 . C h a r a t e r i s t i c s o f I n c l u d e d S t u d i e s ( J a d a d S c o r e 3 )

N a t u r a l

M e d i c i n e

F i r s t A u t h o r a n d Y e a r

C o u n t r y

D u r a t i o n

T y p e

S a m p l e

S i z e

A g e

D i a g n o s t i c S y s t e m

O u t c o m e M e a s u r e s

D e t a i l s o f

I n t e r v e n t i o n

G i n k g o b i l o b a

V e l l a s e t a l .

( 2 0 1 2 )

F r a n c e

5 y e a r s

R a n d o m i s e d , p

a r a l l e l - g r o u p ,

d o u b l e - b

l i n d , p l a c e b o - c o n -

t r o l l e d c l i n i c a l t r i a l

n

2 8 5 4

7 0

y e a r s D S M - I

V ,

N I N C D S - A D R D A

,

M M S E a n d C D R

D S M - I

V a n d N I N C D S -

A D R D A

2 4 0 m g / d a y E G b 7 6 1 :

P l a c e b o

I h l e t a l . ( 2 0 1 2 )

U k r a i n e

2 4 w e e k s R a n d o m i s e d c o n t r o l l e d t r i a l

n

4 0 4

( n

3 3 3

f o r A D )

5 0

y e a r s N I N C D S - A R D R A

S K T

, N P I

, N P I c a r e g i v e r

d i s t r e s s s c o r e , A D C S -

C G I C

, A D L - I

S ,

D E M Q O L - p r o x y a n d

V F T

2 4 0 m g / d a y E G b 7 6 1 :

P l a c e b o

L e B a r s e t a l .

( 2 0 0 2 )

G e r m a n y ,

U S A

5 2 w e e k s R a n d o m i z e d ,

d o u b l e - b

l i n d , p l a -

c e b o - c o n t r o l l e d , p a r a l l e l -

g r o u p , m u l t i c e n t e r s t u d y

n

1 2 2

4 5

y e a r s I C D - 1

0 a n d D S M - I

I I - R

A D A S - C o g a n d G E R R I 1 2 0 m g / d a y E G b 7 6 1 :

P l a c e b o


( 2 0 0 0 )

G e r m a n y ,

U S A

2 6 w e e k s D o u b l e - b l i n d , p l a c e b o - c o n -

t r o l l e d , x e d d o s e ,

p a r a l l e l -


n

2 4 4

4 5

y e a r s I C D - 1

0 a n d D S M - I

I I - R

A D A S - C o g ,

G E R R I a n d

C G I C

1 2 0 m g / d a y E G b 7 6 1 :

P l a c e b o


( 1 9 9 7 )

U S A

5 2 w e e k s R a n d o m i z e d d o u b l e - b

l i n d , p l a -



n

3 2 7

4 5

y e a r s I C D - 1

0 a n d D S M - I

I I - R

A D A S - C o g ,

G E R R I a n d

C G I C

1 2 0 m g / d a y e x t r a c t o f G

b i l o b a : P l a c e b o

S c h n e i d e r e t a l . ( 2 0 0 5 )

U S A


p l a c e b o - c o n -

t r o l l e d , d o u b l e - b

l i n d , p a r a l -

l e l - g r o u p , m u l t i c e n t e r t r i a l

n

5 1 3

6 0

y e a r s M M S E

A D A S - C o g a n d A D C S -

C G I C

1 2 0 m g o r 2 4 0 m g / d a y

e x t r a c t o f G i n k g o :

P l a c e b o

N a p r y e y e n k o e t a l .

( 2 0 0 9 )

U k r a i n e




l i n d , p a r a l -

l e l - g r o u p , m u l t i c e n t e r t r i a l

n

3 9 5

( n

2 1 4

f o r A D )

5 0

y e a r s N I N C D S - A R D R A a n d

M M S E

S K T

, V F T

, C D T

, N P I

,

H R S D

, a n d G B S -

A D L

2 4 0 m g / d a y E G b 7 6 1 :

P l a c e b o

D e K o s k y e t a l .

( 2 0 0 8 )

U S A

6 . 1 y e a r s R a n d o m i z e d ,

d o u b l e - b

l i n d , p l a -



n

5 2 3

7 5

y e a r s D S M - I

V a n d C D R

D S M - I

V

2 4 0 m g / d a y e x t r a c t o f

G i n k g o : P l a c e b o

M a z z a e t a l .

( 2 0 0 6 )

I t a l y




l i n d s t u d y

n

7 6

5 0

8 0 y e a r s D S M - I

V a n d S K T

S K T

, M M S E

, a n d C G I

1 6 0 m g / d a y e x t r a c t o f

G i n k g o : P l a c e b o :

d o n e p e z i l ( 5 m g / d a y )

K a n o w s k i a n d H o e r r

( 2 0 0 3 )

G e r m a n y

2 4 w e e k s M u l t i - c e n t e r ,

d o u b l e - b

l i n d ,

d o n e p e z i l - c o n t r o l l e d , r a n -

d o m i z e d t r i a l

n

2 2 2

> 5 4

y e a r s D S M - I

I I - R ,

S K T

, M M S E

,

a n d M A D R S

A D A S - C o g ,

S K T

, C G I ,

a n d N A B

2 4 0 m g / d a y E G b 7 6 1 :

P l a c e b o

K a n o w s k i e t a l . ( 1 9 9 7 )

G e r m a n y

2 4 w e e k s P r o s p e c t i v e , r a n d o m i z e d ,

d o u -

b l e - b l i n d , p l a c e b o - c o n t r o l l e d ,

m u l t i - c e n t e r s t u d y

n

2 1 6

> 5 4

y e a r s D S M - I

I I - R ,

S K T

, M M S E

,

a n d M A D R S

C G I I t e m 2 , S K T

, a n d

N A B

2 4 0 m g / d a y E G b 7 6 1 :

P l a c e b o


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T a b l e 1 . ( C o n t i n u e d )

N a t u r a l

M e d i c i n e

F i r s t A u t h o r a n d Y e a r

C o u n t r y

D u r a t i o n

T y p e

S a m p l e

S i z e

A g e

D i a g n o s t i c S y s t e m

O u t c o m e M e a s u r e s

D e t a i l s o f

I n t e r v e n t i o n

Y a n c h e v a e t a l .

( 2 0 0 9 )

B u l g a r i a


d o u b l e - b

l i n d ,

a c t i v e - c o n t r o l l e d , m u l t i - c e n -

t e r t r i a l

n

9 6

5 0

y e a r s N I N C D S - A D R D A

, C D T

, a n d

S K T

S K T

, N P I

, A D L s u b -

s c o r e o f G B S , H R S D

,

C D T a n d V F T

2 4 0 m g / d a y E G b 7 6 1 :

d o n e p e z i l ( i n i t i a l l y

5 m g , a f t e r 4 w e e k s

1 0 m g / d a y ) : E G b 7 6 1

& d o n e p e z i l c o m -

b i n e d ( s a m e d o s e s )

M a u r e r e t a l . ( 1 9 9 7 )

G e r m a n y

3 m o n t h s D o u b l e - b l i n d , r a n d o m i z e d ,

p l a -

c e b o - c o n t r o l l e d p a r a l l e l -

g r o u p d e s i g n

n

2 0

5 0

8 0 y e a r s N I N C D S - A R D R A a n d D S M -

I I I - R

S K T

, t r a i l m a k i n g t e s t ,

A D A S , a n d C G I

2 4 0 m g / d a y E G b 7 6 1 :

P l a c e b o

S . o f c i n a l i s

A k h o n d z a d e h e t a l .

( 2 0 0 3 ) ( S O )

I r a n

4 m o n t h s P a r a l l e l g r o u p , p l a c e b o c o n -

t r o l l e d , m u l t i c e n t e r t r i a l

n

4 2

b e t w e e n

6 5 a n d

8 0 y e a r s

N I N C D S - A R D R A

, A D A S -

c o g a n d C D R

A D A S - c o g a n d C D R - S

B S a l v i a o f c i n a l i s e x t r a c t ,

6 0 d r o p s / d a y : P l a c e -

b o

M . o f

n i n a l i s

B u r n s e t a l .

( 2 0 1 1 )

U K

1 2 w e e k s D o u b l e - b l i n d , p a r a l l e l - g r o u p ,

p l a c e b o - c o n t r o l l e d , r a n d o m -

i z e d t r i a l

n

1 1 4

> 6 0

y e a r s N I N C D S - A R D R A

P A S , N P I a n d B l a u Q O L

s c a l e

F u z h i s a n e x t r a c t ( 1 0 m g /

d a y ) : P l a c e b o


( 2 0 0 3 ) ( M O )

I r a n

4 m o n t h s P a r a l l e l g r o u p , p l a c e b o c o n -

t r o l l e d , m u l t i c e n t e r t r i a l

n

4 2

b e t w e e n

6 5 a n d

8 0 y e a r s


, A D A S -

c o g , a n d C D R

A D A S - c o g a n d C D R - S

B F u z h i s a n e x t r a c t ( 1 0 m g /


H u p e r z i n e A

X u e t a l .

( 1 9 9 9 )

C h i n a

6 0 d a y s

M u l t i c e n t e r , p r o s p e c t i v e , d o u -

b l e - b l i n d , d o u b l e - m

i m i c

,

p a r a l l e l , p o s i t i v e c o n t r o l l e d

a n d r a n d o m i z e d t r i a l

n

6 0

N / A


H D S - R

, I A D L

, G B S -

S D S , T E S S

, C G I ,

C C G I , e t c .



R a i e t a l . ( 2 0 1 1 )

U S A

1 6 w e e k s M u l t i c e n t e r , 3 - a r m , r

a n d o m i z e d ,

d o u b l e - b


t r o l l e d , d o s e - e s c a l a t i o n t r i a l

n

2 1 0

5 0

y e a r s N I N C D S - A R D R A a n d

M M S E

A D A S - c o g , N P I

, A D L

a n d M M S E



C . s a t i v u s

( S a f f r o n )


( 2 0 1 0 )

I r a n

1 6 w e e k s D o u b l e - b l i n d , p l a c e b o - c o n -

t r o l l e d , p a r a l l e l - g r o u p t r i a l

n

4 6

> 5 5

y e a r s D S M - I

V ,


,

a n d M M S E

A D A S - C o g a n d C D R -

S B



C u r c u m i n

B a u m e t a l .

( 2 0 0 8 )

H o n g K o n g 6 m o n t h s d o u b l e - b


t r o l l e d , r a n d o m i z e d t r i a l

n

3 4

5 0

y e a r s N I N C D S - A D R D A

M M S E



F u z h i s a n

( f o r m u l a )

B i e t a l . ( 2 0 1 1 )

C h i n a


d o u b l e - b

l i n d , p l a -

c e b o - c o n t r o l l e d p i l o t s t u d y

n

2 2

N / A


, D S M

- I V

,

C D R

, a n d M M S E

A D A S - C o g a n d N P I



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the study participants, location, design, diagnoses, interventions and outcome measures inthe included studies.

Thirteen studies were identi ed for Ginkgo intervention, of which 2 were excludedbecause they did not involve an ITT analysis ( Kanowski et al. , 1997 ; Maurer et al. , 1997 ),2 were repeated publications ( Le Bars et al. , 2000; 2002 ) and 1 lacked a placebo control(Yancheva et al. , 2009 ). Eight studies were nally included in quantitative synthesis,namely meta-analysis for the comparison between Ginkgo and placebo, of which 6 studiedthe effect of treatment ( Le Bars et al. , 1997 ; Kanowski and Hoerr , 2003 ; Schneider et al. ,2005 ; Mazza et al. , 2006 ; Napryeyenko et al. , 2009 ; Ihl et al. , 2012 ) and two studied thepreventative effect of AD ( DeKosky et al. , 2008 ; Vellas et al. , 2012).

Records iden ed throughdatabase searching

(MEDLINEn =498EMBASEn =675

Cochrane n =106PsycINFO n =393)

S c r e e n

i n g

I n c

l u d e

d

E l i g

i b i l i t y

I d e n

c a

o n

Addi onal records iden edthrough other sources

(n =0)

Records a er duplicates removed(n =524)

Records screened(n =524)

Records excluded

(n =489not complying to theinclusion criteria in

Methods)

Full-text ar cles assessedfor eligibility

(n =35, Jadads scores 3)

Full-text ar cles excluded,not indica ng demen a of

AD type(n =14)

Studies included in qualita ve synthesis(n =13, Ginkgo interven on;

n =8, interven ons of Salvia o ffi cinalis ,Melissa o ffi cinalis , Crocus sa vus , curcumin,

huperzine A, Fuzhisan)

Studies included in quan ta vesynthesis (meta-analysis)

(n =6, Ginkgo for AD treatment;n =2, Ginkgo for AD preven on)

Records excluded for

Ginkgo interven on(n =2 not ITT analysis:

Maurer et al . (1997) andKanowski et al . (1997);

n =1 not versus placebo:Yancheva et al . (2009);

n =2 repeated publica ons:Le Bars et al . (2000, 2002)

Figure 1. Study ow diagram.


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Risks of Bias in Included Studies

Firstly, all trails were screened by Jadad s 5-point criteria, which demonstrated whether randomization, double-blind and dropouts were described. Figures 2 and 3 summarize thegeneral risk of bias of the included studies with Jadad s scores 3 , the former illustratesthe percentages of judgment across all included studies and the latter presents the judgment for each domain in individual study shown as a cross-tabulation. If insuf cient detail wasreported of what happened in the study, the judgment for a speci c domain was considered

as unclear risk of bias.Fourteen studies described a random component in the sequence generation process

using a computer for random number generation ( Kanowski et al. , 1997 ; Le Bars et al. , 1997 ;Maurer et al. , 1997 ; Akhondzadeh et al. , 2003a ,b; 2010 ; Kanowski and Hoerr , 2003 ;Schneider et al. , 2005 ; Mazza et al. , 2006 ; DeKosky et al. , 2008 ; Napryeyenko et al. , 2009 ;Burns et al. , 2011 ; Yancheva et al. , 2009 ; Ihl et al. , 2012 ; Vellas et al. , 2012 ). In 12 trials,allocation concealment was achieved by central allocation, sequentially numbered drugcontainers of identical appearance and sequentially numbered, opaque, sealed envelopes(Kanowski et al. , 1997 ; Le Bars et al. , 1997 ; Maurer et al. , 1997 ; Akhondzadeh et al. , 2003a ,b;

Figure 2. Risk of bias graph presented as percentages across all included studies.

Figure 3. Risk of bias summary presented as listed items for individual trial.

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2010 ; Kanowski and Hoerr , 2003 ; Schneider et al. , 2005 ; Mazza et al. , 2006 ; DeKosky et al. ,2008 ; Napryeyenko et al. , 2009; Burns et al. , 2011 ; Yancheva et al. , 2009 ; Ihl et al. , 2012 ;Vellas et al. , 2012 ). Ten studies were assessed as appropriate double-blinding of participantsand personnel both for performance and outcome assessment ( Kanowski et al. , 1997 ; Le Barset al. , 1997 ; Kanowski and Hoerr , 2003 ; Schneider et al. , 2005 ; Mazza et al. , 2006 ; DeKoskyet al. , 2008 ; Napryeyenko et al. , 2009 ; Yancheva et al. , 2009 ; Burns et al. , 2011 ; Vellas et al. ,2012 ). Three studies provided detailed information for double blinding during performancebut insuf cient information for the blinding of outcome assessment ( Akhondzadeh et al. ,2003a ,b; 2010 ). All studies mentioned the number of participants completingor withdrawingfrom the trials, but eight studies reported the dropouts due to inef cacy of intervention in highrisk of attrition bias ( Le Bars et al. , 1997 , 2000 , 2002 ; Xu et al. , 1999; Mazza et al. , 2006 ;Baum et al. , 2008 ; Yancheva et al. , 2009 ; Burns et al. , 2011 ). Three studies were in high risk of bias due to selective outcome reporting ( Xu et al. , 1999 ; Baum et al. , 2008 ; Bi et al. , 2011 ).Eight studies had a potential source of bias related to the speci c study design used ( Maurer et al. , 1997 ; Xu et al. , 1999; Akhondzadeh et al. , 2003a ,b; 2010 ; Bi et al. , 2011 ; Yancheva et al. , 2009 ; Burns et al. , 2011 ).

Description of the Reported Natural Medications

The reported natural medications in RCTs involve S. of cinalis , Melissa of cinalis , C.sativus , curcumin, huperzine A, Fuzhisan ( Bi et al. , 2011 ) and Gingko biloba . Akhond-

zadeh et al. (2003a ,b; 2010 ) reported that the extract of C. sativus , S. of cinalis extract or Melissa of cinalis produced a signi cantly better outcome on cognitive functions (ADAS-Cog, CDR-SB) than the placebo over a 4-month period. Baum et al. (2008 ) reportedcurcumin showed a non-signi cant tendency of a slower decline rather than an improve-ment in cognition (MMSE) in a 6-month pilot clinical trial. Huperzine A, extracted from the Chinese herb Huperzia serrata , did not show cognitive bene t (ADAS-Cog) at the doseof 200 g BID in patients with mild to moderate AD, the 400 g BID dose showed non-signi cant tendency of cognitive enhancement as measured by the ADAS-Cog and theMMSE ( Ra i et al. , 2011 ). In the other trial for huperzine at the dose of 200 g BID (Xuet al. , 1999 ), also no signi cant difference was found vs. the placebo for the psychological

assessment. It did, however, reduce the pathological changes of the free oxygen radicals inthe plasma and erythrocytes of patients with AD. Fuzhisan, a Chinese herbal formula, wasreported to signi cantly improve ADAS-Cog scores, NPI scores and the regional cerebralmetabolic rate of glucose consumption (rCM-Rglc), which suggests that Fuzhisan treat-ment may have a positive effect on cognition, behavior functions, and rCM-Rglc in mild-to-moderate AD patients ( Bi et al. , 2011 ). Ginkgo was the most frequently studied naturalmedicine for AD and was subjected to quantitative assessment with meta-analysis.

Quantitative Assessment of the Ef cacy of Ginkgo Intervention

Two meta-analyses were performed for evaluating the treatment ef cacy of Ginkgo vs. theplacebo. Six studies ( N 1294 ) employed cognition scales as primary endpoint outcomes


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for the assessment of Ginkgo intervention vs. the placebo. SMD in the meta-analysis for combining continuous data of cognition scales showed Ginkgo had better cognition out-comes than the placebo control using a random effect model. In total, the SMD between the

cognition scores of Ginkgo and placebo was 1.62 (95% CI: 2.69 to 0.56) shown inFig. 4. There was signi cant heterogeneity in the results across the studies (test for het-erogeneity, p < 0 :00001 , I 2 98 % ), however every individual study showed a positiveeffect of Ginkgo treatment, except for the study of Schneider 2005. 4 studies ( N 910 )showed the estimated effects showing favorable effects for the use of Ginkgo on activitiesof daily living in AD patients. Overall, SMD of Ginkgo vs. placebo was 1.55 (95% CI:

2.55 to 0.55) and signi cant heterogeneity was detected (test for heterogeneity, p < 0 :00001 , I 2 96 % ), which is shown in Fig. 5. Each included study showed the effect-favoring Ginkgo on activities of daily living in AD patients.

One meta-analysis was performed for assessing the preventative effect of Ginkgo

against AD ( N 5884 ), considering subgroups of participants with different clinical de-mentia ratings (CDR 0 ; N 3894 or CDR 0 :5 ; N 1990 ) at baseline (Fig. 6). Thedichotomous data of AD incidence was analyzed with random-effects and Mantel-Haenszelmethods. In the subgroup of CDR 0 and CDR 0 :5 at baseline, the risk ratio (RR) isrespectively 1.09 (95% CI: 0.89 to 1.35) and 1.02 (95% CI: 0.80 to 1.29). Overall, the RRis 1.06 (95% CI: 0.92 to 1.22) between Gingko and the placebo. There is no signi cant heterogeneity across these two studies (test for heterogeneity: overall p 0 :49 , I 2 0 % ;subgroup p 0 :65 , I 2 0 % ). Both trials reported that Ginkgo extract did not reduce therisk of progression to AD compared with the placebo. Funnel plots were checked but asymmetry measurement was not applicable since there were fewer than 10 studies in eachmeta-analysis, because the test power was too low to distinguish chance from a real effect (Sterne et al. , 2011) (data not shown).

Figure 4. Forest plot of cognition outcomes (ADAS-cog, SKT): Ginkgo vs. placebo.

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Discussion

We performed this systematic review to show the natural medications that are involved indocumented RCTs up to date. The quality of literature was evaluated by Jadad s score andCochrane assessing tool for risk of bias. Most of the clinical studies scored 2 or lessaccording to Jadad s appraisal system, which are considered as low-quality trials. Eventhough 21 studies with Jadad s score above 3 (inclusive), 13 studies had at least onedomain with a high risk of bias in accordance with Cochrane appraisal criteria, of which 8studies reported the dropouts due to inef cacy of intervention in high risk of attrition bias(Le Bars et al. , 1997 ; 2000 ; 2002 ; Xu et al. , 1999 ; Mazza et al. , 2006 ; Baum et al. , 2008 ;Yancheva et al. , 2009 ; Burns et al. , 2011 ), 3 studies were in high risk of reporting bias dueto selective outcome reporting ( Xu et al. , 1999 ; Baum et al. , 2008 ; Bi et al. , 2011 ), and 8studies had a potential source of bias related to the speci c study design used ( Maurer et al. , 1997 ; Xu et al. , 1999 ; Akhondzadeh et al. , 2003a ,b; 2010 ; Yancheva et al. , 2009 ; Bi

Figure 5. Forest plot of activities of daily living in AD patients: Ginkgo vs. placebo.

Figure 6. Forest plot of incidence of AD: Ginkgo vs. placebo.


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et al. , 2011 ; Burns et al. , 2011 ). The risk exists that the true intervention effect can beoverestimated or underestimated in these reports.

S. of cinalis (Akhondzadeh et al. , 2003a ), M. of ninalis (Akhondzadeh et al. , 2003b ),C. sativus (Akhondzadeh et al. , 2010), curcumin ( Baum et al. , 2008 ), Fuzhisan ( Bi et al. ,2011 ) were reported in RCTs for patients with AD, however of which the scienti c basisfor clinical recommendation is questionable because minimal bene ts were observed andthe methodological quality of the available trials was poor due to a small sample size,poorly de ned participants, improper analysis of the impact of withdrawals, selectivereporting, etc. Burns et al. (2011 ) reported that the aromatherapy of M. of ninalis is not superior to the placebo or donepezil in the treatment of agitation in people with AD.Huperzine A is a natural cholinesterase inhibitor-derived from the Chinese herb Hperziaserrata that may compare favorably in systematic ef cacy to cholinesterase inhibitorscurrently in use for AD. However, there is no demonstrable cognitive effect in patients withmild to moderate AD ( Xu et al. , 1999; Ra i et al. , 2011 ). Of note, Ra i et al. (2011 ) andXu et al. (1999 ) suggested that huperzine A at a high dose (400 g BID) showed limitedsigns of cognitive enhancement as measured by the ADAS-Cog and MMSE, which in-dicating that huperzine A may have a possible short-term symptomatic bene t, but thisrequires con rmation in additional studies. Apart from the RCT-related natural medica-tions, Panax ginseng has been considered to have potential protective and neurotrophiceffects on the cognitive function for a long time. But no available RCTs with Jadad score

3 were documented for ginseng until now. Prospective open-label studies indicated that

ginseng treatment was found to be safe and feasible as a cognitive enhancer in AD patients(Heo et al. , 2008 ; 2011 ; Lee et al. , 2008 ). Further double-blinded RCTs with larger samples of patients and longer treatment duration are expected to con rm the ef cacy of ginseng intervention for AD.

The meta-analyses of pooling results from separate studies were performed on severaloutcomes related to the treatment or prevention of AD patients with Ginkgo. The pooleddata was analyzed using random effects model to avoid dissimilar treatment effect acrossstudies. Heterogeneity determines the validity of the conclusions of meta-analyses, as thelevel of heterogeneity increases the justi cation for an integrated result becomes moredif cult (Walker et al. , 2008 ). Figures 4 and 5 show the forest plots for the outcome of

cognition and activities of daily living in the treatment of AD. In Fig. 4, the estimatedeffects are on the same side of the unit line except for the study of Schneider et al.(2005 ). The con dence intervals of other studies overlap to an acceptable extent. Thesestudies reported a bene t of Ginkgo but Schneider s study suggested that there was nostatistical signi cance between the placebo and Ginkgo. Schneider s trial did not showthe ef cacy of Ginkgo, however, the lack of decline of the placebo patients may havecompromised the sensitivity of the trial to detect a treatment effect. Thus, the studyremains inconclusive with respect to the ef cacy of Ginkgo ( Schneider et al. , 2005 ).Thus the signi cant heterogeneity in Fig. 4 was caused largely due to Schenider s study.A similar result of meta-analysis on the outcome of cognition was found in the subgroupof patients with AD by Weinmann et al. (2010 ), which also showed a statisticallysigni cant advantage of Ginkgo compared to the placebo, despite a huge heterogeneity

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of the clinical trials. In Fig. 5, the con dence intervals of all studies are located on thesame side in favor of Ginkgo. Even though the test for heterogeneity is signi cant, thetendencies favoring Ginkgo on the outcome of activities of daily living in the studiesachieve consistency. It is only a matter of dissimilarity in the favoring degree of indi-vidual results. There are limited systematic reviews published before in assessing theef cacy of natural medicines on AD. Heterogeneity in types of natural medicines, di-agnostic criteria, and outcome measures hindered comprehensive data analysis for nat-ural medicines ( Dos Santos-Neto et al. , 2006 ; Man et al. , 2008 ). This analysis isconsistent with the results of another meta-analysis, which draws the conclusion that Ginkgo has a bene cial effect on the outcome of activities of daily living, but thepotential effect size cannot be con rmed because of signi cant heterogeneity acrossincluded RCTs ( Janssen et al. , 2010 ). Further justi cation for the ef cacy and dosagerequires more rigorous evidence with appropriate sample sizes, clinical settings, dosagearms and experimental durations.

There are RCTs, which were reported for mixed dementia and not included in thisreview speci c for AD. However, the ndings of RCTs for mixed dementia containing ADprovide supporting evidence for better-off outcomes associated with AD. Herrschaft et al.(2012 ) reported that the treatment with Ginkgo extract resulted in a signi cant and clini-cally relevant improvement in cognition, psychopathology, functional measures andquality of life in 410 outpatients with mild to moderate dementia in a 24-week trial.Scripnikov et al. (2007 ) reported that Ginkgo improved the neuropsychiatric symptoms

(apathy/indifference, anxiety, irritability/lability, depression/dysphoria and sleep/nighttimebehavior) of 400 dementia patients in a 22-week trial.To indicate the underlying mechanism, two studies directly compared a cholinesterase

inhibitor donepezil with Ginkgo in the treatment of patients with mild to moderate AD inan explorative manner ( Mazza et al. , 2006 ; Yancheva et al. , 2009 ). No signi cant dif-ference was found between Ginkgo and donepezil, suggesting that the ef cacy of Ginkgomay be explained by its modulatory in uence on the cholinergic system. The Ginkgoextract, such as EGb761, used in RCTs, mainly contain avone glycosides and terpenelactones including ginkgolides and bilobalide. Many lines of pre-clinical experiments in-dicate the potential mechanisms. Ginkgo may exert effects on AD due to either a free

radical scavenging activity or the inhibition of pro-in ammatory pathways or the poten-tiation of the cell stress response ( Mancuso et al. , 2012 ). EGb761 has been shown inseveral preclinical reports to increase nearly all aspects of impaired neuroplasticity (long-term potentiation, spine density, neuritogenesis, neurogenesis). While all three fractions of constituents (ginkgolides, avonoids, bilobalide) seem to be active, the avonoids andspeci cally the aglycone isorhamnetin seem to be most relevant ( Muller et al. , 2012 ).Ginkgo extract was suggested to have long-term regulatory effects on mitochondria.Ginkgo has a selective effect on the activities of mitochondrial enzymes that assemble theelectron transport system. The avonoids, bilobalide and some of the ginkgolides had a high protective capacity, indicating that a combination of several compounds withinstandardized Gingko extracts contribute disproportionately for these protective effects(Eckert , 2012 ). Rendeiro et al. (2012 ) suggest that avonoids have a potential in


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modulating neuronal function and thereby in uencing memory, learning and cognitivefunction. Absorbed avonoids and their metabolites may interact with and modulatecritical signaling pathways, transcription factors and gene and/or protein expression, whichcontrol memory and learning processes in the hippocampus.

Figure 6 represents the meta-analysis for assessing the prevention effect of Ginkgoagainst AD, in which the RRs developing AD of these two included studies are onthe similar location (RR value is 1) of the unit line and con dence intervals overlap toa large extent. It suggests that there is no signi cant effect between Ginkgo andplacebo when preventing AD occurrence. The included two studies for the effect esti-mate of AD prevention were regarded as high-quality RCTs, between which there is nosigni cant heterogeneity in a statistical test for heterogeneity. There is no link betweenGinkgo intervention and subsequent AD incidence, and the risks of AD in the Ginkgogroup compared with the placebo group were not proportional with time. Ginkgo cannot be recommended for the purpose of preventing AD judging from the existing evidence.The clinical trial performed by Snitz et al. (2009 ) reported that, compared with theplacebo, Ginkgo did not result in less cognitive decline in older adults with normalcognition or with mild cognitive impairment. Dodge et al. (2008 ) reported that Ginkgoneither altered the risk of progression from normal to Clinical Dementia Rating 0.5, nor protected against a decline in memory function. These might imply that Ginkgo cannot prevent AD progression because Ginkgo fails to hinder the cognitive decline.

It is seemingly contradictory that Ginkgo cannot decrease AD incidence and prevent

AD development yet has a bene cial effect on the treatment outcomes of cognition andactivities of daily life. The two trials ( DeKosky et al. , 2008 ; Vellas et al. , 2012 ) included inthe prevention effect are the most powerful trials and methodologically the most robust studies on the use of Gingko in AD patients so far. Five trials ( Le Bars et al. , 1997;Kanowski and Hoerr , 2003; Mazza et al. , 2006 ; Napryeyenko et al. , 2009 ; Ihl et al. , 2012 )involved in the treatment analysis on cognition outcome with positive results are smalltrials except for one neutral result ( Schneider et al. , 2005 ), thus we cannot exclude thepossibility of publication bias. Considering the small trials were included and the existenceof heterogeneity across studies, the meta-analyses for treatment outcomes of Gingkocompared to placebo should be treated with caution for readers. However, since Ginkgo

was reported to have the potential treatment effect on the outcomes of AD in most availableRCTs, we speculated that Ginkgo may help established AD patients with cognitivesymptoms but cannot prevent AD from neurodegenerative progression.

One weakness of this review is that unpublished data was not speci cally included,thus, despite a comprehensive search strategy employed to identify published studies, therecould be unpublished studies we did not identify. And this review includes only Englishliterature, which may not represent all of the evidence and can induce a language bias. Dueto the complicated and inconsistent nature of the documented RCTs, the other potentiallimitation of this review is that conducting a meta-analysis does not overcome problemsthat were inherent in the design and execution of the primary studies. We assessed the biasof studies but this cannot be corrected in the meta-analysis for statistical results. And thescope of categories of natural medicines and AD outcome measures are open to future

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modi cations. More high-quality RCTs with rigorous methodology in exploring naturalmedicines are desirable to achieve a solid con rmation for clinical decision-making.

Acknowledgments

M.Y. and D.D.X. contributed equally to the whole process including database searching,data analysis and interpretation and paper preparation. W.C.C. carried out design of sys-tematic review, scrutiny of the research methodology and preparation of this paper. Y.Z.and X.L. were involved in RCT appraisal, approval of statistics. R.H. participated inapproval of RCT appraisal and critical revision of this paper. Financial support was pro-vided by Tangdu Hospital of the Fourth Military Medical University, China.

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A Systematic Review on Natural Medicines for the Prevention and Treatment of Alzheimer's Disease...

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