SYSTEMATIC REVIEW

published: 05 June 2020

doi: 10.3389/fnagi.2020.00121

The Comparative Efficacy of Multiple

Interventions for Mild Cognitive
Impairment in Alzheimer’s Disease: A
Bayesian Network Meta-Analysis
Xin Lai, Hao Wen, Yu Li, Liming Lu and Chunzhi Tang*
Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China

Background: Mild cognitive impairment (MCI) is the early phase of Alzheimer’s disease
(AD). The aim of early intervention for MCI is to decrease the rate of conversion from MCI
to AD. However, the efficacy of multiple interventions in MCI, and the optimal methods
of delivery, remain controversial. We aimed to compare and rank the treatment methods
for MCI in AD, in order to find an optimal intervention for MCI and a way to prevent or
delay the occurrence of AD.
Edited by: Methods: Pair-wise and network meta-analysis were conducted to integrate the
Woon-Man Kung,
Chinese Culture University, Taiwan treatment effectiveness through direct and indirect evidence. Four English databases
Reviewed by: and three Chinese databases were searched for international registers of eligible
Tae-Hun Kim, published, single or double blind, randomized controlled trials up to September 31st
Kyung Hee University, South Korea
2019. We included nine comparative interventions: pharmacological therapies which
Roger C. Ho,
National University of incorporated cholinesterase inhibitors (ChEI), ginkgo, nimodipine, and Chinese medicine;
Singapore, Singapore non-pharmacological therapies comprising of acupuncture, music therapy, exercise
Dafin F. Muresanu,
Iuliu Haţieganu University of Medicine therapy, and nutrition therapy; and a placebo group. The primary outcome was the
and Pharmacy, Romania Mini-Mental State Examination (MMSE) score. The secondary outcome was the AD
*Correspondence: Assessment Scale-cognitive subscale (ADAS-cog).
Chunzhi Tang
[email protected] Results: Twenty-eight trials were eligible, including 6,863 participants. In the direct
meta-analysis, as for the Mini-Mental State Examination scale, the ChEIs (MD: −0.38;
Received: 17 December 2019 95% CI: −0.74, −0.01), Chinese medicine (MD: −0.31; 95% CI: −0.75, 0.13), exercise
Accepted: 09 April 2020
Published: 05 June 2020 therapy (MD: −0.50; 95% CI: −0.65, −0.35), music therapy (MD: −1.71; 95% CI:
Citation: −4.49, 1.07), were statistically more efficient than placebo. For AD Assessment
Lai X, Wen H, Li Y, Lu L and Tang C Scalecognitive subscale outcome, ChEIs (MD: 1.20; 95% CI: 0.73, 1.68), Acupuncture
(2020) The Comparative Efficacy of
Multiple Interventions for Mild
(MD: 1.36; 95% CI: 1.28, 1.44), Chinese medicine (MD: 0.61; 95% CI: 0.49, 0.73)
Cognitive Impairment in Alzheimer’s and exercise (MD: 0.61; 95% CI: 0.49, 0.73) were better than placebo. In the network
Disease: A Bayesian Network meta-analysis, the MMSE outcome ranked music therapy (59%) as the best and
Meta-Analysis.
Front. Aging Neurosci. 12:121. Acupuncture (26%) as second. Nutrition and Ginkgo treatment had the lowest rank
doi: 10.3389/fnagi.2020.00121 among all interventions. For ADAS-cog outcome, acupuncture (52) ranked the best.

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Lai et al. Interventions for MCI in Alzheimer’s Disease

Conclusion: Among the nine treatments studied, music therapy appears to be the
best treatment for MCI, followed by acupuncture. Our study provides new insights into
potential clinical treatments for MCI due to AD, and may aid the development of guidelines
for MCI in AD.
Keywords: acupuncture, Alzheimer’s disease, mild cognitive impairment, multiple interventions, music therapy,
network meta-analysis

INTRODUCTION treatments for MCI that help to improve cognitive function and
prevent or delay the occurrence of AD.
Mild cognitive impairment (MCI) has been defined as a
“transitional” state to describe individuals who are not
cognitively “active” for their age, but who would not meet
METHODS
a clinical diagnosis of early dementia (Brendan and Kelley, Search Strategy
2015). It is an intermediate clinical condition with a number of Four English databases (Medline [via Ovid], Embase [via Ovid],
sub-types and multiple pathologies (Petersen, 2004; Rountree Cochrane Library [Central Register of Controlled Trials], and
et al., 2007). Web of Science [via Ovid]) and three Chinese databases
MCI is currently an area of considerable clinical and research (China Science Journal Citation Report [VIP], China National
interest because a large proportion of patients with MCI develop Knowledge Infrastructure [CNKI], and Wanfang) were searched
Alzheimer’s disease (AD). In order to delay the progress of AD, for all relevant citations published from the date of the respective
it is important to recognize the key neurobiological difference database onset to September 31st 2019. We established search
between MCI and AD. Several journal articles have demonstrated strategies which combined subject word (keyword) and random
that MCI patients progress to AD at a higher rate (10–15% per words related to MCI, interventions of interest (drug therapy,
year) than normal elderly patients (1–3% per year). Furthermore, diet/lifestyle therapy, physical activity/exercise, complementary
two-thirds of patients with AD were previously recognized as therapies, sham/placebo) and randomized controlled trial
having MCI (Rubin et al., 1989; Almkvist et al., 1998; Wolf et al., (RCT). Furthermore, the reference lists of the included
1998; Kluger et al., 1999; Petersen et al., 1999, 2001; Collie and studies were manually reviewed to look for additional relevant
Maruff, 2000; Morris et al., 2001). Therefore, patients who have manuscripts. The specific search strategies are shown in
MCI are considered to be at a greater risk for AD. Unfortunately, Supplementary Datasheet 1.
treatment options for AD are currently suboptimal, especially in
the advanced stage of AD where the brain damage is irreversible. Selection and Exclusion Criteria
Thus, it is important to start treatment for AD as early as possible, The RCTs which met the following criteria were included:
and intervention during the MCI stage may prevent or delay the (1) participants had mild cognitive impairment due to
occurrence of AD. AD; (2) the interventions were pharmacological therapies
Several treatments have been used for MCI, including including Cholinesterase inhibitors, Memantine, Ginkgo biloba,
cholinesterase inhibitors (ChEIs), complementary and Huperzine A, Piracetam, Nimodipine, and Chinese medicine, or
alternative medicine, lifestyle and nutrition interventions, non-pharmacological therapies including acupuncture, music
and Chinese medicine. However, which of these interventions therapy, lifestyle therapy, exercise therapy, and nutrition therapy;
work, and to what extent, remains unknown. (3) the comparisons were placebo, no intervention, usual care
Pairwise meta-analysis have previously been conducted to control, or other comparable interventions; (4) the study
assess the efficacy of ChEIs, including donepezil, galantamine, included at least one cognitive performance outcome measure in
and rivastigmine (Cooper et al., 2013; Tricco et al., 2013; the form of either the MMSE (Mini-Mental State Examination)
Matsunaga et al., 2019). These studies suggested that ChEIs have a or ADAS-cog (AD Assessment Scale-cognitive subscale) and the
low efficacy in the treatment of MCI and many safety issues were efficacy of the studies must include mean changes from baseline
raised. Therefore, before using ChEIs for MCI, other methods to endpoint.
should be considered. Studies with the following characteristics were excluded: (1)
Other studies (Andreas et al., 2015; Liang et al., 2018) have participants with a diagnosis of MCI due to diseases other than
suggested that physical exercise and computerized cognitive AD; (2) irrelevant outcomes or deficient data; and (3) case
training could improve cognitive function and neuropsychiatric reports, review articles, clinical protocols, conference abstracts,
symptoms. Furthermore, non-pharmacological therapies might and animal experimental studies.
perform more effectively than pharmacological therapies.
However, these studies were incomplete and provide insufficient Data Extraction and Quality Assessment
data, because they were unable to introduce clear hierarchies Two investigators (XL and YL) screened the articles and extracted
among treatments and a number of interventions were not the data and related statistics independently. Basic information
analyzed. Therefore, the aim of this article was to conduct a was organized into a standard table, including information on the
network meta-analysis to thoroughly compare and rank different characteristics of the population, intervention(s), comparison(s),

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Lai et al. Interventions for MCI in Alzheimer’s Disease

treatment duration, event(s), and outcome. The Cochrane Risk of Statistical Analysis
Bias Tool (Savovic et al., 2014) was used by two researchers (XL Firstly, a pair-wise meta-analysis was used to compare the
and YL) to assessed the risk of bias and quality of included trials. compliance of different therapies. By using the Aggregate Data
A third reviewer (HW) was consulted to recheck studies when Drug Information System (ADDIS ver. 1.16.8, available at:
the first two reviewers had disagreements and discrepancies. https://drugis.org/software/addis/index) with a random-effects
model, the odds ratio (OR) was measured for discontinuous
Outcomes outcomes along with 95% credible intervals (CI). Statistical
Our network meta-analysis used Mini-Mental State Examination heterogeneity was calculated in the pair-wise comparisons with
(MMSE) as the primary outcome to measure global cognition, an I 2 statistic and the p-value.
with higher MMSE scores meaning better cognitive function. The Furthermore, we conducted a network meta-analysis. This
second outcome was the AD Assessment Scale-cognitive subscale network meta-analysis was set up with a Bayesian framework
(ADAS-cog), in which lower scores mean better cognitive using the Aggregate Data Drug Information System (ADDIS
function. If the complete data on outcomes were not reported ver. 1.16.8, available at: https://drugis.org/software/addis/index)
in the original article, we contacted authors via email to obtain to determine the cognitive outcomes of nine interventions. This
the raw data, otherwise studies lacking such data were eliminated. software uses the Bayesian framework as a base combined with
The data were independently collected by two reviewers (XL and the Markov chain Monte Carlo method to evaluate research data.
YL) and rechecked by a third investigator (HW). A random-effects model was used to evaluate the effect sizes

FIGURE 1 | Study selection. RCT, randomized controlled trial.

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 TABLE 1 | Characteristics of included studies.
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Lai et al.
References Country Number of people (n) Age (Y) Intervention Comparison Treatment Events Outcomes
duration

Doody et al. (2009) USA DON: 409 55–90 Donepezil (5–10 mg) Placebo 48 w 1. Diarrhea (donepezil: 16.4%; placebo: Primary: MMSE;
PLA: 412 3.4%) Secondary: modified ADAS-cog
2. Muscle spasms (donepezil: 13.3%;
placebo: 1.8%)
3. Insomnia (donepezil: 8.2%;
placebo: 4.4%).
Salloway et al. (2004) USA DON: 133 55–90 Donepezil (5–10 mg); Placebo Placebo 24 w 1. Diarrhea (donepezil: 27%; placebo: Modified ADAS-cog
PLA: 137 10%)
2. Abnormal dreams (donepezil 23%;
placebo: 4%), 3. insomnia (donepezil:
11%; placebo 5%).
Winblad et al. (2008) USA, Canada GAL: 494 ≥50 Galantamine (16–24 mg); Placebo 24 m 1. Nausea (GAL: 29%; PAL: 10%) Modified ADAS-cog;
PLA: 496 Placebo 2. Diarrhea (GAL: 15%; PAL: 9%) ADCS-ADL
3. Insomnia (GAL: 10%; PAL: 7%)
Winblad et al. (2008) USA, Canada GAL: 532 ≥50 Galantamine (16–24 mg); Placebo 24 m 1. Nausea (GAL: 29%; PAL: 10%) Modified ADAS-cog;
PLA: 526 2. Diarrhea (GAL: 15%; PAL: 9%) ADCS-ADL
3. Insomnia (GAL: 10%; PAL: 7%)
Wilkinson et al. (2002) UK, South RIV: 55 ≥50 Rivastigmine (12 mg) Donepezil 12 w 1. Nausea (RIV: 41.8%; DON: 10.7%) Primary: MMSE
Africa, Don: 56 (5–10 mg) 2. Vomiting (RIV: 23.6%; DON: 7.1%) Secondary: ADAS-cog
Switzerland 3. Headache (RIV: 18.2%; DON: 7.1%)
Howard and Roger Australia, RIV: 227 ≥50 Rivastigmine (6–36 mg) Placebo 26 w 1. Nausea (RIV: 48.0%; PLA: 14.0%) Primary: MMSE;
(2007) Canada, Italy, PLA: 222 2. Vomiting (RIV: 30.0%; PLA: 6.3%) Secondary: ADAS-cog
South Africa, 3. Anorexia (RIV: 18.5%; PLA: 2.4%)
UK
4

Dong et al. (2012) China GIN: 58 60–85 Ginkgo glycosides (9.6 mg Placebo 1y Not mentioned MMSE
PLA: 55 tid)
Xiao et al. (2011) China GIN: 54 55–85 Ginkgo glycosides (19.2 mg Placebo 6m Not mentioned MMSE
PLA: 44 tid)
Aisen et al. (2008) USA VB: 240 ≥50 Folate: 5 mg, Vitamin B6: Placebo 18 m 1. Depression (VB: 27.9%; PAL: 17.8%) Primary: MMSE;
PLA: 169 25 mg, Vitamin B12: 1 mg Secondary: ADAS-cog
2. Restlessness (VB: 12.1%; PAL:
8.3%) 3. Hyperhidrosis (VB: 9.6%;
PAL: 4.1%)
Petersen et al. (2005) USA, Canada VE: 257 55–90 Vitamin E: 2,000 IU Placebo 36 m 1. Diarrhea (VE: 10.2%; placebo: 6.6%) Primary: MMSE
PLA: 259 2 Insomnia (VE: 3.1%; placebo: 1.9%) Secondary: ADAS-cog
3. Nausea (VE: 1.2%; placebo: 1.9%).
Sun et al. (2007) Taiwan Multivitamin: 45 ≥50 Multivitamin supplement* + Placebo 26 w 1. Muscle pain (multivitamin: 11.1%; Primary: MMSE

Interventions for MCI in Alzheimer’s Disease

PLA: 44 Mecobalamin: 0.5 mg PAL: 6.8%) Secondary: ADAS-cog
2. Insomnia (multivitamin: 8.9%;
PAL: 9.1%)
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3. Delirium (multivitamin: 8.9%;

PAL: 2.3%)
Dysken et al. (2014) / VE: 152 60–75 2,000 IU vitamin E Placebo 4y Not mentioned Primary: MMSE
PLA: 152 Secondary: ADAS-cog
Tian et al. (2019) China CM: 174 ≥50 Qinggongshoutao 27 g; Placebo 52 w Upper respiratory tract infection, Primary: MMSE
PLA: 70 EGb761 160 mg diarrhea, constipation, urinary tract Secondary: ADAS-cog
infection, and increased blood glucose
Zhou et al. (2007) China CM: 42 53–79 Shenyin Oral Liquid Placebo 12 m Not mentioned MMSE
PLA: 37

(Continued)
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Lai et al.
TABLE 1 | Continued

References Country Number of people (n) Age (Y) Intervention Comparison Treatment Events Outcomes
duration

Wei et al. (2012) China CM: 24 45–80 Danshen, Sanqi Placebo 12 w CM: stomachache (2) PLA: urinary tract Primary: MMSE
PLA: 23 infection (2) Secondary: ADAS-cog
Miao et al. (2012) China CM: 45 40–85 CM; 200 ml Placebo 12 w Not mentioned Primary: MMSE
PLA: 48 Secondary: ADAS-cog
Suzuki et al. (2013) Japan Exercise: 50 ≥65 Multicomponent exercise Placebo 6m Not mentioned Primary: MMSE
PLA: 50 (bi-weekly 90-min): aerobic Secondary: ADAS-cog
exercise, muscle strength
training, postural balance
retraining, and dual-task
training
Lautenschlager et al. Australia Exercise: 48 ≥50 ≥150 min of Placebo 18 w 1. Cardiovascular problems (EXE: ADAS-cog
(2008) PLA: 52 moderate-intensity physical 6.3%; PLA: 1.9%)
activity per week 2. Stroke or transient ischemic attack
(EXE: 2.1%; PLA: 1.9%)
Grace et al. (2013) Hong Kong Exercise: 7 ≥60 Computer-assisted EL Placebo 3m Not mentioned MMSE
PLA: 6 memory training;
Therapist-led EL memory
training group
Tsai et al. (2013) USA Taichi: 28 ≥60 Taichi (3 sessions a week) Placebo: 20 w Not mentioned MMSE
PLA: 27 attention
control group
Doi et al. (2017) Japan Music: 67 ≥70 Music: playing percussion Control: health 40 w No injuries reported MMSE
5

Con: 67 instruments at weekly 60-min education

sessions classes
Li et al. (2015) Taiwan Music: 20 ≥60 Music: Mozart’s Sonata (KV Placebo 6m Not mentioned MMSE
PLC: 21 448) and Pachelbel’s Canon,
listening with headphones for
30 min daily in the morning
and before sleep
Cai et al. (2019) China Music: 25 60–74 Music: 1–1.5 h music therapy, Placebo 3m Not mentioned MMSE
PLC: 25 3 times a weeks
Yang et al. (2019) China ACU: 108 55–85 Acupuncture: 30 min twice a Placebo 6m Not mentioned ADAS-cog
PLC: 105 week (at an interval of 2–4
days)
Jia et al. (2017) China ACU: 43 50–85 Acupuncture: 30 min, 3 times Donepezil: 28 w Not mentioned ADAS-cog
ChEIs: 44 weekly 5–10 mg

Interventions for MCI in Alzheimer’s Disease

Zhu et al. (2015) China ACU: 30 46–75 Acupuncture: Acupuncture Nimodipine 8w Not mentioned MMSE
NIM: 30 and Moxibustion (30 min 30 mg, 3 times
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each, 6 times weekly) a day

Chen (2011) China ACU: 80 55–85 Acupuncture: Acupuncture Placebo 8w Acu: fainting during acupuncture MMSE
PLC: 75 (30 min, 3 times weekly) treatment 10 Drug: gastrointestinal
reaction 9
Zheng et al. (2008) China CM: 30 / Nimodipine 30 mg, 3 times a Chinese 12 w Not mentioned MMSE
NIM: 30 day medicine:
once a day

*Containing: iron ferrous 60 mg, nicotinamide 10 mg, calcium carbonate 250 mg, riboflavin 2 mg, thiamine mononitrate 3 mg, calcium pantothenate 1 mg, ascorbic acid 100 µg, iodine 100 µg, copper 150 µg, vitamin B12 3 µg, vitamin
A 4,000 IU, and vitamin D3 400 IU.
ACU, acupuncture; ChEIs, cholinesterase inhibitors; CM, Chinese medicine; Con, control; d, days; m, months; NIM, nimodipine; PLC, placebo; w, weeks; y, years.
Lai et al. Interventions for MCI in Alzheimer’s Disease

in this network meta-analysis. Random-effect model attempted RESULTS

to generalize findings beyond the included studies by assuming
that the selected studies are random samples from a larger Study Identification and Selection
population (Cheung et al., 2012). The mean difference (MD) Overall, a total of 13,522 studies were identified from the
was the effect size for continuous outcomes. The models used seven electronic databases using the search strategy, and 198
to estimate the effect size in ADDIS were “consistency” and relevant full-text articles were evaluated for eligibility. There were
“inconsistency.” The consistency model aims to evaluate effect 169 citations excluded, including 17 duplicates, 21 conference
sizes of the interventions, which was used to calculate the abstracts, 28 clinical protocols, 14 non-RCTs, and 90 unrelated
ranking probabilities for the whole group of interventions. intervention or outcome articles. Ultimately, 28 studies including
Node-splitting analysis helps to determine the consistency test 6,863 patients were clinical eligible to be included in this network
with an inconsistency model. For instance, a consistency model meta-analysis (Figure 1). The characteristics of the selected
was chosen when the p-value of the node-splitting analysis studies were listed in Table 1.
was >0.05. If the p-value of the node-splitting analysis was
<0.05, an inconsistency model was selected. In order to evaluate Study Quality
the convergence of the model, the potential scale reduction The Cochrane Risk of Bias Tool was used to assess the quality
factor (PSRF) was used. If the PSRF value was close to 1, the of all 28 trials included in our study (Figure 2 shows the
convergence of the model was more desirable. If the PSRF summary risk of bias for selected studies). Among the 28 trials, 19
value was <1.2, it was still considered as acceptable. For each (66%) represented a random sequence generation process using
intervention, the ranking probabilities were estimated for every a computer random number generator or a random number
treatment at every possible rank. table. Fourteen trials (48.3%) described the use of allocation

FIGURE 2 | Quality assessment of included studies.

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Lai et al. Interventions for MCI in Alzheimer’s Disease

concealment methods, and 22 trials (75.9%) described the Pair-Wise Meta-Analysis

blinding methods for researchers and participants. Acupuncture, We conducted a classic pair-wise meta-analysis using a random-
music therapy, and exercise therapy are non-pharmacologic effects model to synthesize studies with the same pair of
therapies, therefore some participants and researchers involved interventions. All interventions, except for nimodipine, had at
in these studies were not able to be blinded. Six trials (21.4%) had least one placebo controlled trial. As for the MMSE outcome,
an uncertain risk of outcome assessment and 25 trials (86.2%) had the ChEIs (MD: −0.38; 95% CI: −0.74, −0.01), Chinese medicine
a low risk of attrition bias. (MD: −0.31; 95% CI: −0.75, 0.13), exercise therapy (MD: −0.50;

FIGURE 3 | (A) The network structure of the analyzed treatment comparisons for the outcome of MMSE. (B) Rank probability of cognitive effects of MMSE. ACU,
acupuncture; CM, Chinese medicine; CHEI, cholinesterase inhibitors; ET, exercise therapy; MT, music therapy; NIM, nimodipine; NT, nutrition therapy.

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Lai et al. Interventions for MCI in Alzheimer’s Disease

95% CI: −0.65, −0.35), music therapy (MD: −1.71; 95% CI: probability (59%) of being the best treatment for MCI, followed
−4.49, 1.07), were worse than placebo,and other interventions by Acupuncture (26%) and then exercise (7%).
were statistically more efficient than placebo. For ADAS-cog
outcome, ChEIs (MD: 1.20; 95% CI: 0.73, 1.68), Acupuncture
(MD: 1.36; 95% CI: 1.28, 1.44), Chinese medicine (MD: 0.61; Secondary Outcome: ADAS-cog
95% CI: 0.49, 0.73) and exercise (MD: 0.61; 95% CI: 0.49, 0.73) In relation to the secondary outcome (ADAS-cog score), 17 trails
were better than placebo. The detailed results of the pair-wise and 6 treatments were involved, 2 arms of Acupuncture, 6 arms
meta-analysis are shown in Supplementary Datasheet 2. of ChEIs, 3 arms of Chinese medicine, 2 arms of exercise therapy
and 4 arms of nutrition therapy (presented in Figure 4A). After
Node-splitting analysis,we adopted the consistency model to
compare these different interventions. Chinese medicine (MD:
Network Meta-Analysis −2.72; 95% CI: −4.83, −0.56), Acupuncture (MD: −2.84; 95%
Primary Outcome: MMSE CI: −5.61, −0.34), exercise therapy (MD: −0.71; 95% CI: −3.12,
We ran a network meta-analysis to thoroughly compare and
1.68), and ChEIs (MD: −0.88; 95% CI: −2.23, 0.53) were better
assess different treatment rankings for MCI, the network of
than placebo. Nutrition therapy (MD: 1.43; 95% CI: −0.34, 3.14)
MMSE include 23 trails and 15 interventions,the network plot
was least effective compared to other interventions and placebo
presented in Figure 3A. Node-splitting analysis was used to
(shown in Table 3). The ranking probability of ADAS-cog is
assess consistency, and all p-values between the direct and
presented in Figure 3B. Acupuncture ranked the best (52%), it
indirect effects were > 0.05. A PSRF value of 1 indicated that
might be the most effective way to change the ADAS-cog score.
the model was convergent and the result was stable. Therefore,
the consistency model was selected for the subsequent network
analysis.
The network meta-analysis for the primary outcome (MMSE)
is shown in Table 2. In terms of efficacy music therapy (MD: Adverse Events
1.74; 95% CI: 0.21, 3.26), Acupuncture (MD: 1.22; 95% CI:−0.97, Out of 28 trials, 13 trails reported adverse events occurred,
3.39), and exercise therapy (MD: 0.52; 95% CI: −1.22, 2.28) 14 trails did not mention whether there was adverse events
achieved better than placebo. Ginkgo (MD: −0.40; 95% CI: and one trial stated no injures reported (Table 1). 9 out of
−2.34, 1.57) and nutrition therapy (MD: −0.75; 95% CI: −2.04, 13 trials reported adverse events related to gastrointestinal
0.61) were significantly less effective than other interventions discomforts such as diarrhea, nausea, vomiting and anorexia,
and placebo. Other pharmacological therapies including Chinese these interventions were mainly ChEIs, nutrition therapy and
medicine (MD: 0.27; 95% CI: −0.96, 1.52) and ChEIs (MD: Chinese medicine. 8 out of 13 trails reported insomnia as adverse
0.46; 95% CI: −1.02, 1.96) showed a slight improvement in effect which mainly related to ChEIs and nutrition interventions.
MMSE scores; however, their efficacy in MCI needs further 1 out of 13 trails reported cardiovascular problem due to exercises
investigation. The ranking probability of MMSE is presented in intervention and 1 out of 13 trials reported Acupuncture-fainting
Figure 3B, the results showed that music therapy had the highest due to Acupuncture intervention.

TABLE 2 | The consistency model of MMSE, comparisons should be read from left to right.

ACU −0.93 (−3.25, −0.76 (−3.44, −0.70 (−3.47, −1.62 (−4.51, 0.52 (−2.13, −1.18 (−3.38, −1.95 (−4.51, −1.22 (−3.39,
1.38) 1.92) 2.19) 1.26) 3.19) 1.02) 0.59) 0.97)
0.93 (−1.38, 3.25) CM 0.19 (−1.74, 0.25 (−1.86, −0.68 (−2.95, 1.45 (−0.50, −0.22 (−2.46, −1.02 (−2.79, −0.27 (−1.52,
2.13) 2.35) 1.65) 3.44) 1.96) 0.77) 0.96)
0.76 (−1.92, 3.44) −0.19 (−2.13, ChEI 0.07 (−2.25, −0.86 (−3.35, 1.26 (−0.82, −0.43 (−3.19, −1.19 (−3.13, −0.46 (−1.96,
1.74) 2.33) 1.60) 3.40) 2.34) 0.82) 1.02)
0.70 (−2.19, 3.47) −0.25 (−2.35, −0.07 (−2.33, ET −0.93 (−3.51, 1.22 (−1.12, −0.48 (−3.40, −1.27 (−3.41, −0.52 (−2.28,
1.86) 2.25) 1.69) 3.47) 2.37) 0.95) 1.22)
1.62 (−1.26, 4.51) 0.68 (−1.65, 0.86 (−1.60, 0.93 (−1.69, Ginkgo 2.14 (−0.34, 0.47 (−2.58, 3.40) −0.33 (−2.67, 0.40 (−1.57, 2.34)
2.95) 3.35) 3.51) 4.51) 2.06)
−0.52 (−3.19, −1.45 (−3.44, −1.26 (−3.40, −1.22 (−3.47, −2.14 (−4.51, MT −1.71 (−4.43, −2.48 (−4.45, −1.74 (−3.26,
2.13) 0.50) 0.82) 1.12) 0.34) 1.08) −0.41) −0.21)
1.18 (−1.02, 3.38) 0.22 (−1.96, 0.43 (−2.34, 0.48 (−2.37, −0.47 (−3.40, 1.71 (−1.08, NIM −0.77 (−3.42, −0.03 (−2.35,
2.46) 3.19) 3.40) 2.58) 4.43) 1.88) 2.30)
1.95 (−0.59, 4.51) 1.02 (−0.77, 1.19 (−0.82, 1.27 (−0.95, 0.33 (−2.06, 2.67) 2.48 (0.41, 4.45) 0.77 (−1.88, 3.42) NT 0.75 (−0.61, 2.04)
2.79) 3.13) 3.41)
1.22 (−0.97, 3.39) 0.27 (−0.96, 0.46 (−1.02, 0.52 (−1.22, −0.40 (−2.34, 1.74 (0.21, 3.26) 0.03 (−2.30, 2.35) −0.75 (−2.04, Placebo
1.52) 1.96) 2.28) 1.57) 0.61)

Treatments; Efficacy (mean overall change, SMD [95% Crl]).

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FIGURE 4 | (A) The network structure of the analyzed treatment comparisons for the outcome of ADAS-cog. (B) Rank probability of cognitive effects of ADAS-cog.

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Lai et al. Interventions for MCI in Alzheimer’s Disease

TABLE 3 | The consistency model of ADAS-cog, comparisons should be read from left to right.

ACU 0.10 (−3.17, 3.61) 1.97 (−0.65, 4.76) 2.14 (−1.35, 5.88) 4.26 (1.28, 7.53) 2.84 (0.34, 5.61)
−0.10 (−3.61, 3.17) CM 1.85 (−0.61, 4.35) 2.02 (−1.23, 5.16) 4.15 (1.38, 6.87) 2.72 (0.56, 4.83)
−1.97 (−4.76, 0.65) −1.85 (−4.35, 0.61) ChEI 0.16 (−2.61, 2.94) 2.30 (0.04, 4.51) 0.88 (−0.53, 2.23)
−2.14 (−5.88, 1.35) −2.02 (−5.16, 1.23) −0.16 (−2.94, 2.61) ET 2.13 (−0.83, 5.09) 0.71 (−1.68, 3.12)
−4.26 (−7.53, −1.28) −4.15 (−6.87, −1.38) −2.30 (−4.51, −0.04) −2.13 (−5.09, 0.83) NT −1.43 (−3.14, 0.34)
−2.84 (−5.61, −0.34) −2.72 (−4.83, −0.56) −0.88 (−2.23, 0.53) −0.71 (−3.12, 1.68) 1.43 (−0.34, 3.14) Placebo

Treatments, efficacy (mean overall change, SMD [95% Crl]).

DISCUSSION acupuncture is associated with activation in motor-related

brain regions as shown in functional magnetic resonance
This study is the first network meta-analysis performed imaging (fMRI) (Chen et al., 2008, 2012; Chae et al., 2009).
on potential pharmacological and non-pharmacological Other studies supplemented that Acupuncture is able to
treatments for MCI, and has incorporated the most regulate the emotional components of the pain matrix, and
comprehensive data. The Bayesian statistical methods that inducing brain activation which provides a neurobiological
we used allowed us to rank many different treatments by basis of acupuncture (Shangjie et al., 2014; Shan et al., 2018).
measuring comparable probability and then reporting them Research also suggests that acupuncture can activate resting
as the best, the second best, and so on. Through this method, brain networks, which incorporate anti-nociceptive, memory,
we found that among all interventions, both pharmacological and emotion brain regions. Our network meta-analysis
therapies (ChEIs, ginkgo, nimodipine, and Chinese medicine) suggests that music therapy is the optimal intervention to
and non-pharmacological therapies (acupuncture, music treat MCI patients and improve their cognitive function,
therapy, exercise, and nutrition therapy), music therapy whereas acupuncture was the second best option.Further
and acupuncture were better than other treatments. Some research is required to assess other interventions not
pharmacological treatments like CHEIs such as donepezil, included in this meta-analysis. A recent study found that
galantamine, and rivastigmine showed a slight efficacy to mindfulness therapy improved inflammatory biomarkers
improve MMSE scores and cognitive function, but have in patients with MCI (Ng et al., 2020). This provides an
many safety issues which require further clarification and interesting perspective on the current management paradigms
study. In addition, ginkgo and nutrition therapy might be for MCI.
ineffective for MCI, which are thus not strongly recommended The adverse events reports showed that some participants
in clinical medicine. experienced gastrointestinal reactions and insomnia due to
Music therapy is one of the non-pharmacological therapies ChEIs, nutrition and Chinese medicine interventions. However,
which incorporates active and passive therapy. Active music none of these events was related to cognitive distress. Other
therapy can be defined as therapeutic music activities which small samples such as exercise and Acupuncture reported therapy
involve active participation by clients, such as singing, dancing related adverse effects such as cardiovascular problems and
with music, playing an instrument, composing, and discussing Acupuncture fainting respectively. Music therapy didn’t report
clients’ thoughts and feelings in regards to music-related activities any adverse events.
in order to reach the optimal treatment effect. Passive music There were limitations to our study. Firstly, a few RCTs
therapy, on the other hand, means achieving the treatment showed potential bias because of the small number of
effect by listening and enjoying music. Passive music therapy participants and elective reporting. Fortunately, there was
is also called receptive music therapy and is widely used no obvious inconsistency or heterogeneity shown in this
(Chang et al., 2015; Han et al., 2017; Claudia et al., 2019). network meta-analysis, but there is a possibility that some
Previous research has shown that music can activate some brain included articles might have overestimated the effectiveness
regions that govern cognitive function, affective function, and of treatments, and this might have influenced our results.
motor skills, and activate neurological stimulation which may Secondly, a few included reports were non-pharmaceutical
develop new neural networks (Raglio et al., 2014; Mofredj et al., therapies which cannot be blinded to participants, especially
2016). Evidence has shown that, in the context of patients acupuncture. However, blinding of outcome assessment and
with cognitive function decline, music therapy intervention single-blind methodologies should be used where possible to
increases cerebral blood flow and pre-frontal cortex activity reduce the potential for any bias. Thirdly, we have excluded
(Shimizu et al., 2018). some drug interventions because of our selection criterion
Acupuncture has been shown to be a good management of outcome measures, which may influence the strength
option in neurological diseases, with studies demonstrating of evidence.

Frontiers in Aging Neuroscience | www.frontiersin.org 10 June 2020 | Volume 12 | Article 121

Lai et al. Interventions for MCI in Alzheimer’s Disease

CONCLUSION AUTHOR CONTRIBUTIONS

The findings of this comprehensive network meta-analysis CT and LL designed the study. XL, YL, and HW collected
provide some evidence that music therapy and acupuncture the data. XL performed all analysis. XL, YL, and HW
might improve the cognitive function of patients with MCI. wrote the manuscript. All authors contributed to writing of
Our results indicate that music therapy and, to a lesser this manuscript.
extent, acupuncture may be the preferred options for treatment
of MCI. Ginkgo and nutrition therapy do not seem to be FUNDING
adequate as regular treatment options. Our study provides new
insights into the clinical treatments available for MCI, and This work was funded by grants from National Natural Science
may help the development of guidelines for the management Foundation of China (No. 81873375).
of MCI.
SUPPLEMENTARY MATERIAL
DATA AVAILABILITY STATEMENT
The Supplementary Material for this article can be found
All datasets generated for this study are included in the online at: https://www.frontiersin.org/articles/10.3389/fnagi.
article/Supplementary Material. 2020.00121/full#supplementary-material

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Shan, Y., Wang, J., Wang, Z., Zhao, Z., Zhang, M., Xu, J., et al. (2018). Conflict of Interest: The authors declare that the research was conducted in the
Neuronal specificity of acupuncture in Alzheimer’s disease and mild cognitive absence of any commercial or financial relationships that could be construed as a
impairment patients: a functional MRI study. Evid. Based Complement. Altern. potential conflict of interest.
Med. 2018:7619197. doi: 10.1155/2018/7619197
Shangjie, C., Maosheng, X., Hong, L., Jiuping, L., Liang, Y., Xia, L., et al. (2014). Copyright © 2020 Lai, Wen, Li, Lu and Tang. This is an open-access article
Acupuncture at the Taixi(KI3) acupoint activates cerebral neurons in elderly distributed under the terms of the Creative Commons Attribution License (CC BY).
patients with mild cognitive impairment. Neural Regener. Res. 9, 1163–1168. The use, distribution or reproduction in other forums is permitted, provided the
doi: 10.4103/1673-5374.135319 original author(s) and the copyright owner(s) are credited and that the original
Shimizu, N., Umemura, T., Matsunaga, M., and Hirai, T. (2018). Effects of publication in this journal is cited, in accordance with accepted academic practice.
movement music therapy with a percussion instrument on physical and No use, distribution or reproduction is permitted which does not comply with these
frontal lobe function in older adults with mild cognitive impairment: terms.

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