Effect of toki-shakuyaku-san on regional cerebral blood flow in patients with mild cognitive impairment and Alzheimer's disease.
ABSTRACT The aim of this study was to examine the effect of toki-shakuyaku-san (TSS) on mild cognitive impairment (MCI) and Alzheimer's disease (AD) using single-photon emission computed tomography (SPECT). All subjects were administered TSS (7.5 g/day) for eight weeks. SPECT and evaluations using the Mini Mental State Examination (MMSE), Neuropsychiatric Inventory, and Physical Self-Maintenance Scale were performed before and after treatment with TSS. Three patients with MCI and five patients with AD completed the study. No adverse events occurred during the study period. After treatment with TSS, regional cerebral blood flow (rCBF) in the posterior cingulate was significantly higher than that before treatment. No brain region showed a significant decrease in rCBF. TSS treatment also tended to improve the score for orientation to place on the MMSE. These results suggest that TSS could be useful for treatment of MCI and AD.
- SourceAvailable from: PubMed Central[show abstract] [hide abstract]
ABSTRACT: Pharmacologic treatments for Alzheimer's disease include the cholinesterase inhibitors donepezil, galantamine, and rivastigmine. We reviewed their evidence by searching MEDLINE, Embase, The Cochrane Library, and the International Pharmaceutical Abstracts from 1980 through 2007 (July) for placebo-controlled and comparative trials assessing cognition, function, behavior, global change, and safety. Thirty-three articles on 26 studies were included in the review. Meta-analyses of placebo-controlled data support the drugs' modest overall benefits for stabilizing or slowing decline in cognition, function, behavior, and clinical global change. Three open-label trials and one double-blind randomized trial directly compared donepezil with galantamine and rivastigmine. Results are conflicting; two studies suggest no differences in efficacy between compared drugs, while one study found donepezil to be more efficacious than galantamine, and one study found rivastigmine to be more efficacious than donepezil. Adjusted indirect comparison of placebo-controlled data did not find statistically significant differences among drugs with regard to cognition, but found the relative risk of global response to be better with donepezil and rivastigmine compared with galantamine (relative risk = 1.63 and 1.42, respectively). Indirect comparisons also favored donepezil over galantamine with regard to behavior. Across trials, the incidence of adverse events was generally lowest for donepezil and highest for rivastigmine.Clinical Interventions in Aging 02/2008; 3(2):211-25. · 2.65 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist with moderate affinity. Its mechanism of action is neuroprotective and potentially therapeutic in several neuropsychiatric diseases. It has been approved by the FDA for the treatment of moderate to severe Alzheimer's disease (AD) either as a monotherapy or in combination with cholinesterase inhibitors. This review covers key studies of memantine's safety and efficacy in treating moderate to severe AD. It also covers current research into other dementias including but not exclusively mild AD and vascular dementia. Other studies on the efficacy of memantine for other neuropsychiatric diseases are discussed. Memantine is a safe and effective drug that merits further research on several topics. Clinicians should be aware of new studies and potential uses of memantine because of its safety and efficacy.Clinical Interventions in Aging 01/2009; 4:367-77. · 2.65 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia. The terms "donepezil", "rivastigmine", "galantamine", and "mild cognitive impairment" and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64-1.12), and 0.84 (0.57-1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain). The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.PLoS Medicine 12/2007; 4(11):e338. · 15.25 Impact Factor
Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2012, Article ID 245091, 5 pages
Effectof Toki-Shakuyaku-San on RegionalCerebral
BloodFlowinPatients withMildCognitive Impairmentand
Teruyuki Matsuoka,1Jin Narumoto,1Keisuke Shibata,1Aiko Okamura,1Shogo Taniguchi,1
1Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho,
Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
2Department of Psychiatry, Gojouyama Hospital, 4-6-3 Rokujo-Nishi, Nara 630-8044, Japan
Correspondence should be addressed to Teruyuki Matsuoka, email@example.com
Received 12 October 2011; Accepted 18 November 2011
Academic Editor: Paul Siu-Po Ip
Copyright © 2012 Teruyuki Matsuoka et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
The aim of this study was to examine the effect of toki-shakuyaku-san (TSS) on mild cognitive impairment (MCI) and Alzheimer’s
disease (AD) using single-photon emission computed tomography (SPECT). All subjects were administered TSS (7.5g/day) for
eight weeks. SPECT and evaluations using the Mini Mental State Examination (MMSE), Neuropsychiatric Inventory, and Physical
Self-Maintenance Scale were performed before and after treatment with TSS. Three patients with MCI and five patients with AD
completed the study. No adverse events occurred during the study period. After treatment with TSS, regional cerebral blood flow
be useful for treatment of MCI and AD.
Cholinesterase inhibitors (ChEIs) and memantine, an N-
methyl-D-aspartate antagonist, are commonly used in treat-
ment of Alzheimer’s disease (AD). These drugs slow the
progression of the disease and improve cognition, function,
and behavior impairment but often have to be discontinued
because of adverse events [1, 2]. There are no approved
drugs for treatment of mild cognitive impairment (MCI).
A systematic review showed that ChEIs were ineffective in
functions and led to adverse events .
There has been a recent increase in the use of traditional
herbal medicine for treatment of dementia. Yokukan-san has
been shown to improve behavioral and psychological symp-
toms of dementia (BPSD) [4, 5], hachimi-jio-gan improved
cognitive function and activity of daily living (ADL) in AD
, and choto-san was effective for patients with vascular
dementia [7, 8]. Moreover, combination treatment with
kami-untan-to and donepezil improved cognitive function
and increased regional cerebral blood flow (rCBF) in the
bilateral frontal lobes .
disorders but has also been used for treatment of cognitive
impairment based on accumulated evidence of its neuroac-
tive and neuroprotective effects. TSS activates cholinergic
[10–14] and monoaminergic [12, 13, 15] neurons and has a
protective effect on amyloid β [16, 17], an antioxidant effect
[18, 19], and an antiapoptosis action . Several clinical
studies have also suggested that TSS improves cognitive
impairment in dementia, MCI, and poststroke patients [20–
22]. Brain imaging may be useful to examine the effects of
TSS. Therefore, the aim of this study was to identify the
effects of TSS in patients with MCI and AD using single-
photon emission computed tomography (SPECT).
2 Evidence-Based Complementary and Alternative Medicine
2.1. Subjects. The subjects were 13 patients treated at the
Center for Diagnosis of Dementia at the Kyoto Prefectural
University of Medicine. Four patients were diagnosed with
MCI and 9 with AD, based on Petersen et al.  and the
National Institute of Neurological and Communicative Dis-
ease and Stroke-Alzheimer’s Disease and Related Disorders
Association (NINCDS-ADRDA) criteria for probable AD
. We excluded patients with a significant history of psy-
chiatric or neurological disorders (other than MCI and AD),
including stroke, head injury, epilepsy, psychiatric disorders,
alcohol abuse, or a serious medical condition. Participants
had not been prescribed ChEIs or memantine since our
center examines patients who have not been diagnosed with
dementia. This study was approved by the Ethics Committee
of the Kyoto Prefectural University of Medicine. Informed
consent was obtained from all of the patients.
2.2. Study Protocol. Subjects were treated with TSS given
as a daily dose of 7.5g of powder for eight weeks. During
this period, new medications were not introduced. TSS is
registered in the Pharmacopoeia of Japan as Kampo Medi-
cine TJ-23. The TSS used in the study was provided by Tsu-
mura (Tokyo, Japan) and was prepared from the extract of
a mixture of dried plants: 4.0g Paeoniae radix, 4.0g At-
ractylodis lanceae rhizoma, 4.0g Alismatis rhizoma, 4.0g
Hoelen, 3.0g Cnidii rhizome, and 3.0g Angelicae radix. All
subjects underwent magnetic resonance imaging (MRI) or
computed tomography (CT) before treatment. SPECT was
performed before and after treatment.
Cognitive impairment was evaluated using the Mini
Mental State Examination (MMSE)  before and after the
study period. The MMSE has 11 subscales including orien-
tation to time, orientation to place, registration, attention,
recall, naming, repetition, auditory comprehension/com-
mand, reading comprehension, sentence construction, and
constructional praxis. BPSD were evaluated before and aft-
er the study period using the Neuropsychiatric Inventory
(NPI) . The NPI is a caregiver-based clinical instrument
that evaluates 10 domains of neuropsychiatric symptoms in
dementia: delusions, hallucinations, agitation, depression,
anxiety, euphoria, apathy, disinhibition, irritability, and
aberrant motor behavior. The frequency score ranges from 0
to 4 points, and the severity score ranges from 0 to 3 points.
The NPI score for each subscale is created by multiplying
the frequency and severity scores, with a maximum score
of 12. Therefore, the NPI total score ranges from 0 to 120.
Higher scores denote a greater severity of a symptom. ADL
before and after the study period were evaluated using the
Physical Self-Maintenance Scale (PSMS) , which consists
of 6 items related to physical activities: toileting, feeding,
dressing, grooming, ambulating, and bathing. A lower total
score indicates greater impairment of ADL.
2.3. Image Acquisition and Analysis. Brain perfusion SPECT
was performed by intravenous injection of 185MBq of
N-isopropyl-p-[123I]iodoamphetamine (I-123-IMP) (Nihon
Mediphysics, Hyogo, Japan) in subjects seated at rest with
their eyes open. SPECT imaging commenced 22min after
the injection and continued for 16min. A triple-head
gamma camera (Prism Irix, Picker International, Cleveland,
OH, USA) and a low-energy, high-resolution, and parallel
collimator were used. Projection data from each camera were
obtained in a 128×128 formatfor40anglesof 1201 at8sper
angle (voxel size: 2 ×2 ×2mm).
Image analysis was performed using Statistical Paramet-
ric Mapping (SPM) 8 (Wellcome Department of Cognitive
Neurology, University College, London, UK) in Matlab 7.5
(Mathworks Inv., Sherborn, MA, USA). After confirmation
of no significant artifacts due to atrophy using MRI or CT
scans, all SPECT images were anatomically normalized using
the I-123-IMP template (Fujifilm RI Pharma, Tokyo, Japan)
matched to the Montreal Neurological Institute (MNI) tem-
plate. The normalized images were smoothed using a 12-mm
full-width half-maximum (FWHM) isotropic Gaussian ker-
nel. To examine regional differences, the images were scaled
to a mean global cerebral blood flow of 50mL/100g/min.
2.4. Statistical Analysis. A Wilcoxon signed rank test was
used to analyze the changes in MMSE, NPI, and PSMS
scores. Data were analyzed using SPSS 12.0 J for Windows
(SPSS Inc., Chicago, IL, USA). P < 0.05 was considered
statistically significant. A paired t-test was performed to
determine whether TSS affected rCBF in patients with MCI
and AD. The X, Y, and Z coordinates provided by SPM
approximate the MNI brain space. The statistical thresholds
were set to a family-wise error (FWE)-corrected P value of
0.05 at the voxel level.
3.1. Subject Characteristics. Eight of the 13 subjects com-
pleted the study. Five were discontinued because of poor
compliance (n = 3), a move to another area (n = 1),
and refusal to continue (n = 1). None of the subjects had
adverse events. The characteristics of the 8 subjects who
completed the study are shown in Table 1. Six had not been
prescribed with a psychoactive drug, 1 had taken risperidone
(1mg/day), and 1 had taken rilmazafone (0.5mg/day) before
the start of the study. Both subjects continued to take these
drugs during the study.
3.2. Changes in MMSE, NPI, and PSMS Scores. Changes in
MMSE, NPI, and PSMS scores are shown in Table 2. At
baseline, cognitive impairment and BPSD were mild, and
ADL was high. Scores for the MMSE, NPI total, and PSMS
did not change significantly after TSS treatment. Among the
MMSE subscales, the score for orientation to place showed
a tendency to improve (P = 0.025), but the change was
not significant using a Bonferroni correction (P = 0.025 >
0.05/11) (Table 3).
3.3. Paired t-Test Using SPM. The paired t-test showed
a significant increase in rCBF in the posterior cingulate
after TSS treatment compared to before treatment (Table 4).
Evidence-Based Complementary and Alternative Medicine3
Table 1: Clinical characteristics of subjects who completed the
Age at onset, y.o.
Duration of illness, years
77.8 ± 4.9
76.3 ± 4.3
12.0 ± 1.7
AD: Alzheimer’s disease; F: female; L: left; M: male; MCI: mild cognitive
impairment; R: right; SD: standard deviation; y.o.: years old.
Values are shown as a number ratio or as the mean ± SD.
Table 2: Changes in MMSE, NPI and PSMS scores from before to
after TSS treatment for 8 weeks.
mean ± SD
mean ± SD
NPI total score
MMSE: Mini Mental State Examination; NPI: Neuropsychiatric Inventory;
PSMS: Physical Self-Maintenance Scale; SD: standard deviation.
treatment for 8 weeks.
mean ± SD
mean ± SD
Orientation to time
Orientation to place
MMSE: Mini Mental State Examination; SD: standard deviation.
When the statistical thresholds were set to an uncorrected P
at the cluster level, the posterior cingulate was the only brain
region that showed a significant increase in rCBF (Figure 1).
No brain region showed a significant decrease in rCBF.
increased after eight weeks of treatment with TSS. The
MMSE, NPI total, and PSMS scores did not worsen and
TSS treatment tended to improve the score for orientation to
place on the MMSE.
Some clinical studies have demonstrated improvement
in cognitive impairment by TSS in dementia and poststroke
patients. Inanaga et al. reported improvement in orientation
to time and place, spontaneous activity, emotional lability,
and motivation in 80 dementia patients (40 with vascular
dementia, 38 with AD, and 2 with mixed dementia) after
12 weeks of TSS treatment , while Goto et al. demon-
strated that TSS is effective in suppressing impairment of
visuospatial perception and the lower limbs in poststroke
patients . In our subjects, orientation to place tended
to improve while other cognitive impairments and BPSD
were unchanged. These findings are partly consistent with
previous studies and suggest that TSS might be particularly
effective for improvement of spatial perception.
TSS treatment in this study was associated with a change
in rCBF in the posterior cingulate. This brain region plays
an important role in many cognitive functions, including
visuospatial orientation, topokinesis, navigation of the body
in space, self reflection, autobiographical memory, and
assessment of objects in space in terms of first-person ori-
entation . Connections between the posterior cingulate
and the parahippocampus are likely to play a major role
in memory-related functions , and these connections
may be disturbed in MCI and AD [30, 31]. Moreover,
hypofunction in the posterior cingulate is associated with
visuoperceptual deficits in MCI and AD , as well as
disorientation to time and place in AD . In this study,
TSS increased rCBF in the posterior cingulate and improved
orientation to place based on the MMSE. Therefore, TSS
might be useful for treatment of cognitive impairment
associated with the posterior cingulate.
Previous studies have shown that donepezil increases
or maintains rCBF, mainly in the frontal lobes [34–37]. In
contrast, in this study, TSS increased rCBF in the posterior
cingulate. In addition to the cholinergic effect, TSS also has
monoaminergic, antiamyloid, antioxidant and antiapoptosis
effects [10–19]. Collectively, these results suggest that TSS
has different effects on cognitive impairment compared to
might have an additional benefit in treatment of MCI and
The study has several limitations, since it was performed
with an open label design with no control group, the
observation period was short, and the sample size was small.
These limitations may reduce the strength of the results, but
the findings were partly consistent with previous studies.
Moreover, to our knowledge, this is the first study to demon-
strate an effect of TSS on rCBF in patients with MCI and AD.
Treatment with TSS significantly increased rCBF in the pos-
terior cingulate and tended to improve orientation to place
in MCI and AD patients. Therefore, TSS might be useful for
treatment of MCI and AD. Moreover, since the effects of TSS
on rCBF may differ from those of donepezil, combination
4Evidence-Based Complementary and Alternative Medicine
Table 4: Results of paired t-tests.
MNI coordinates at the center of the cluster
Z value at the local
Voxel P value
Cluster P value
Figure 1: Regions showing a significant increase in rCBF after TSS treatment. The statistical thresholds were set to an uncorrected P value
of 0.001 at the voxel level and to a corrected P value of 0.05 at the cluster level.
therapy of TSS and donepezil might be particularly effective.
A study in a large number of MCI and AD patients is needed
to confirm the effects of TSS.
Conflict of Interests
The authors declare that there is no conflict of interests.
This study was supported by a Grant-in-Aid for Young Sci-
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