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第 12 号（2016 年 12 月）

39（1125）

IMPROVEMENT IN COGNITIVE FUNCTION BY SUPPLEMENTCONTAINED PLASMALOGEN FOR HEALTHY JAPANESE― A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY ―Masatomo NAJIMA1), Mitsuhiko MUNEKATA2), Takayuki NAKANO3),
Yoshitaka NADACHI4), Hiroyuki KIMURA5) and Hitoshi NAGATA5)
1) JACTA (Japan Clinical Trial Association)
2) OZ Clinic
3) Kagoshima Immaculate Heart University4) Umeda Jimusho, Ltd.
5) P-Solution Inc.

Abstract
Objective: The objective of this study was to investigate the eﬀectiveness of daily ingestionof two soft capsules, which contain plasmalogen.
Methods: A randomized, placebo-controlled, double-blind study was conducted to evaluate
the cognitive function. The study used MMSE (Mini Mental State Exam), U-K test (UchidaKraepelin test) and subjective reporting of the cognitive function.
Results: From all of 135 applicants, 54 were eliminated due to not meeting inclusion criteria.
Among 81 subjects, 6 were withdrawn (unwell; 2, unexpected business; 3, family
bereavement; 1), and 75 subjects completed the study [Test-1 (0.5 mg) sample = 27: M; 9,
F; 18, Test-2 (0.25 mg) sample= 23: M; 10, F; 13, Placebo= 25: M; 9, F; 16]. After 12
weeks of ingestion, the study showed significant differences in the results of MMSE. On
other hand, the results of U-K test did not show signiﬁcant diﬀerences in any groups. As forthe subjective reporting of the cognitive function in form of a questionnaire, intragroup
analysis of the test product showed significant differences in more than half of the items,
whereas inter-group analysis between the test group and the Placebo showed significant
diﬀerences in 4 to 14 items. In addition, no adverse eﬀects were observed after the ingestionof the test product.
Conclusion: We found out that the ingestion of the supplement containing plasmalogen for
12 weeks contributed to the improvement of some cognitive functions related to language
and situation. In addition, no safety-related matter occurred during the 12-week test period.
Key Words: plasmalogen, cognitive function, MMSE, U-K test

1. INTRODUCTION
Japanese society is now regarded as a super-aging
society since the ratio of elderly people of aged 65 years
or older, to the total population, reached 23% in 2010 1).
Aging not only causes a decline of the motor functionalityof the lower back or knees, but also deteriorates the
cognitive capacity such as memory. The phenomenon
related to the decline of the cognitive capacity such as
forgetfulness or memory deterioration is evident in most,as they get older. However, many elderly people tend tofear that they may become demented when theirforgetfulness becomes a more serious matter, and thisfear eventually makes them worry needlessly about theirforgetfulness. According to the releasing of the Ministryof Health, Labour and Welfare, one in every ﬁve personof 65 years or get older is estimated to become demented

in 2025. To prevent dementia, it is regarded as importantto keep the brain in a healthy condition constantly,
without giving up the prevention of the forgetfulness and/or the decline of memory skill caused by the aging.
It is said that the memory of information is controlled byhippocampus, which is part of the cerebral limbic
system 3). Plasmalogen, on the other hand, is one of thephosphatides existing intravitally, and it functions aslinking fat and protein whilst keeping the function of thecell membrane normal. Plasmalogen counts for about
18% of phosphatide in the human body and it reportedly
has antioxidant properties 4). It was reported in 1999 thatthe amount of plasmalogen at the frontal lobe and the
hippocampus of the brain of an Alzheimer s disease
patient is signiﬁcantly decreased 5). This ﬁnding led to the
supposition that plasmalogen had some relationship in theperception skill of humans, and after that a lot of40 （1126）

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Table 1 Nutritional content of the test samples per 100 g
Item

Test-1 (0.5 mg)

Test-2 (0.25 mg)

Placebo

Energy632 kcal

630 kcal

674 kcalProtein
Lipid
Carbohydrate
Salt equivalent
Vitamin E

30.7 g51.8 g10.7 g0.111 g25900 mg30.6 g51.1 g11.9 g0.102 g25900 mg28.5 g56.7 g12.5 g0.02 g−researchers released study reports that plasmalogen has
a beneﬁcial eﬀect on Alzheimer s disease patients and/or
the dementia patients. However, there are few studies
which focus on the relationship between plasmalogen andthe memory skill of a normal (healthy) person.
Therefore, we conducted a randomized, placebocontrolled, double-blind study to verify the eﬀectivenessof plasmalogen for the memory skill and the cognitive
capacity of healthy human and its safeness, by having thetest subjects ingest the supplement containing
plasmalogen.

2. METHODS
2.1. Trial design
A randomized, placebo-controlled, double-blind study was
conducted with the aid of a fund from P-Solution Inc.
(Tokyo) at JACTA (Tokyo). The study period was 12
weeks, from April 5 th to June 29 th, 2016. This study was
conducted in accordance with the ethical principles of thedeclaration of Helsinki. The study protocol was approvedby the Institutional Review Board of Pharmaceutical Law
Wisdoms (Tokyo). Written informed consent was
obtained from all subjects.
The allocation of the test product to the subjects was
carried out by the person in charge of allocation. The
allocation list was sealed and strictly controlled in a safe
deposit box of JACTA until the end of the study.
2.2. Subject
Healthy subjects participated in the present study. All of
the subjects in this study were public volunteers who had
enrolled in the monitor bank of CROee Inc. (Tokyo),recruited from March through April, 2016.
2.2.1. Inclusion criteria(1) Healthy Japanese males and females aged between 40
and 79 years;(2) Individuals who have cognitive diﬃculties but have notbeen diagnosed with a disease according to the cognitive
function questionnaire (Appendix 1).
2.2.2. Exclusion criteria(1) Individuals undergoing treatment of cognitive
diseases;(2) Individuals on medication, including herbal medicines;(3) Individuals who are pregnant, nursing, or likely to
become pregnant during the trial;(4) Individuals judged to be unsuitable to participate in

the trial by the principle investigator.
2.3. Randomization
From all of 135 applicants, 54 were eliminated according
to the cognitive function questionnaire results. The
inclusion criteria was judged by the principle investigator.
All subjects were sequentially allocated to Group A(n = 26), Group B (n = 28), and Group C (n = 27) using arandom number table. In the process of subject
assignment, background factors such as gender, age, andU-K test (2.5.2.2) were taken into consideration to avoid
biased distribution. Subjects in Group A ingested theplacebo, subjects in Group B ingested test sample-2 (0.25
mg of plasmalogen), and subjects in Group C ingested
test sample- 1 (0.5 mg of plasmalogen) for 12 weeks.
2.4. Description of test foods and blinding
The test product was prepared by P-Solution Inc. The
amount of daily intake was 2 soft capsules (1 soft capsuleweighs 270 mg, therefore 2 soft capsules weigh 540 mg).
The Placebo does not include plasmalogen. Table 1
shows the nutritional contents of the samples. All three
types of soft capsules were indistinguishable in shape,
color, or taste. Soft capsules were managed by theidentiﬁcation symbol. All involved were blinded.
2.5. Experimental procedures
2.5.1. Experimental protocol
Subjects consumed 2 soft capsules of the supplement with
hot or cold water every day for 12 weeks. Subjects were
instructed as follows: to take the assigned foods as
indicated; to maintain their usual lifestyle and habits; toavoid excessive amounts of food, drink, or alcohol; tomaintain a daily record of their physical condition andmemory loss occurrences during the test period; and tosend the diary to the study coordinator.
2.5.2. Outcome
According to the schedule shown in Table 2, we
measured parameters on efficacy and safety. These
assessments were conducted upon pre-intervention andpost-intervention.
2.5.2.1. MMSE (Mini Mental State Exam)
For mental state, the Mini Mental State Examination( MMSE ) 6) was used (Appendix 2). MMSE tests a
number of diﬀerent mental abilities, including a person smemory, attention, and language. The overall score was
evaluated (out of 30).

診療と新薬・第 53 巻

Table 2Term
Item
Informed consent
Selection and/or allocation
MMSE
U-K test
Subjective reporting
Ingestion of test foods
Log

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Schedule for the study.

Screening

Pre trial

Test period

test

6w

12 w

●
●
●

●
●
●

●
●
●

●
●

● : Implementation↔ : Daily practice during the test period

2.5.2.2. U-K test (Uchida-Kraepelin test)
To calculate ability, the Uchida-Kraepelin test ( U-K
test ) 7）was used. The U-K test is a serial addition test,
which requires takers to perform calculations as fast andaccurately as possible within 30 min. This was achieved
using pre-printed paper containing 15 lines of random,
single-digit, horizontally aligned numbers. For eachminute of the test, the subject was instructed to begin a
new line regardless of their position on the current line.
Each line contained an excess of calculations such thatthe subjects were not able to finish any line for aparticular minute before being prompted to move on to
the start of the next line by the examiner s prompt. We
evaluated sum up scores in 7 grades, with a higher grade
indicating a better result.
2.5.2.3. Subjective reporting
Further, subjective reporting of the cognitive function
was observed by a questionnaire as the primary outcome.
The questionnaire covered 27 items (Appendix 3).
Responses to each question were rated on an ordinalscale of 0 to 4, with 2 representing the baseline status,and higher scores indicating better results.
2.5.2.4. Safety
To evaluate the safety of the test foods, adverse eventswere collected by means of a written questionnaireduring the study. Safety was evaluated as a secondary
endpoint.
2.6. Data analysis
A full analysis set was adopted in the present study andno sample size design was used. All statistics wereexpressed as mean ± standard deviation (SD).
We evaluated intragroup comparison of MMSE, U-K
test, and subjective reporting by using the paired t-test.
Student s t-test was used for intergroup comparisons of
the measured value at week 0, 6, and 12, and changes
from the baseline (⊿0-6 w and ⊿0-12 w). One-way
analysis of variance was used to compare subject s
backgrounds among groups.
Multiplicity according to the occasions was not adjusted.
Any subjects with missing values were eliminated fromthe analysis. Statistical analyses were performed using

Statcel 4 (Yanai, 2015), and Excel Tokei 2015 (SSRI).
The results were considered signiﬁcant at a < 5% level inthe two-sided test.

3. RESULTS
3.1. Participant demographics
The 81 subjects were randomly assigned to intervention
groups and made a start with ingestion. 6 werewithdrawn (unwell; 2, unexpected business; 3, family
bereavement; 1), and 75 subjects completed the study.
Thus, data obtained from 75 subjects (Test-1 group; 27,
Test-2 group; 23, Placebo group; 25) were used for
efficacy analysis (Fig. 1). There were no significant
differences in gender ratio, age, and U-K test amonggroups (Table 3).
3.2. MMSE
The result of MMSE is shown in Fig. 2 and Table 4.
Significant increases were observed in the intragroup
analysis of Test-1 and Test-2 at week 12, respectively.
Whereas the intragroup analysis of Placebo increased
significantly at week 6. There were no significant
differences in the intergroup analysis of Test-1 versus
Placebo, or Test-2 versus Placebo.
3.3. U-K test
Fig. 3 and Table 4 depict the results of the overall
evaluation of the U-K test. No signiﬁcant diﬀerence wasyielded in the intragroup analysis of Test-1, Test-2, andPlacebo. Concerning the intergroup analysis, only thecomparison of the measurement grade of week 6 between
Test-1 and Placebo tended to diﬀer.
3.4. Subjective reporting
The results of subjective condition assessments areshown in Table 5. Regarding the intergroup analysis ofchanges between Test-1 and Placebo, or Test-2 andPlacebo, significant differences were observed in #1(Test-1, Test-2), #5 (Test-1), #7 (Test-1, Test-2), #8(Test-1), #12 (Test-1), #13 (Test-1), #17 (Test-1, Test2), #18 (Test-1), #25 (Test-1), #26 (Test-2), and #27(Test-1, Test-2) at week 6. Whilst in #1 (Test-1), #2(Test-1, Test-2), #4 (Test-1, Test-2), #5 (Test-1, Test2), #8 (Test-1, Test-2), #12 (Test-1), #15 (Test-2), #16

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Assessed for eligibility (n = 135)
〔M: 51, F: 84〕

Enrollment

Excluded (n = 54) 〔M: 22, F: 32〕¨Did not meet inclusion criteria (n = 54)¨Declined to participate (n = 0)
¨Other reasons (n = 0)
Randomized (n = 81)〔M: 29, F: 52〕

Group A
Allocated to Placebo(n = 26) 〔M: 9, F: 17〕¨Received allocatedintervention (n = 26)

Allocation¨Did not receive allocatedintervention (n = 0)

Lost to follow-up (n = 0)
Discontinued intervention(n = 1)〔M: 0, F: 1〕

Follow-Up¨Being unwell (n = 1)〔M: 0, F: 1〕

Group B

Group C

Allocated to Test-2 (0.25 mg)(n = 28)〔M: 11, F: 17〕¨Received allocatedintervention (n = 28)¨Did not receive allocatedintervention (n = 0)

Allocated to Test-1 (0.5 mg)(n = 27)〔M: 9, F: 18〕¨Received allocatedintervention (n = 27)¨Did not receive allocatedintervention (n = 0)

Lost to follow-up (n = 0)
Discontinued intervention(n = 5)〔M: 1, F: 4〕¨Unexpected business (n = 3)
〔M: 1, F: 2〕

Lost to follow-up (n = 0)
Discontinued intervention (n = 0)

¨Being unwell (n = 1) 〔M: 0, F: 1〕¨Family bereavement (n = 1)
〔M: 0, F: 1〕

Analysed (n = 25)〔M: 9, F: 16〕

Analysis¨Excluded from analysis (n = 0)

Analysed (n = 23)〔M: 10, F: 13〕¨Excluded from analysis (n = 0)

Analysed (n = 27)〔M: 9, F: 18〕¨Excluded from analysis (n = 0)

Fig. 1 Flow diagram of subject disposition

Table 3 Subject demographics
Item

Unit

Test-1 (0.5 mg)

Test-2 (0.25 mg)

Placebop-value

Subjects
Male: Female ＊numbers
numbers
years
grade

27
9:18
57.0 ± 10.7
4.4 ± 1.6

23
10:13
58.8 ± 10.5
4.0 ± 1.8

25
9:16
57.2 ± 9.5
4.0 ± 1.5

−
0.758
0.795
0.575

Age ＊
U-K test ＊mean ± SD＊

No signiﬁcant diﬀerence(Test-2), #17 (Test-2), #20 (Test-2), #21 (Test-2), #23(Test-2), #24 (Test-1, Test-2), #26 (Test-2), and #27(Test-1, Test-2) at week 12. In the comparison of Test-1
versus Placebo, 10 items showing a signiﬁcant diﬀerence
at week 6 decreased to 6 items at week 12, whereas 4
items showing a signiﬁcant diﬀerence at week 6 expanded
to 14 items at week 12 in that of Test-2 versus Placebo.

3.6. Safety
No adverse eﬀects associated with the test product wereobserved in the course of the reporting.

4. DISCUSSION
We conducted a randomized, placebo-controlled, doubleblind study for examining the efficacy of a food

診療と新薬・第 53 巻

0w

6w

28.5

第 12 号（2016 年 12 月）

12 w

43（1129）

0w
5

＊＊
＊＊

28

6w

12 w

‡ (p = 0.072)

4.8

＊

4.6

27.5

4.4
27
4.2
26.5

4

26
25.5
Score

3.8
Test-1

3.6

PlaceboTest-2＊:p < 0.05, ＊＊:p < 0.01 against baseline

Test-1:p < 0.01 between-group diﬀerence in Test-1 versus Placebo.

Fig. 3 U-K test

Table 4

MMSE
〈score〉

U-K test〈grade〉

Placebo‡Fig. 2 MMSE

Item
〈unit〉

Test-2

Results of test analyses

Time point

Test-1（0.5 mg）（n = 27）1）

Test-2（0.25 mg）
1）（n = 23）

Placebo（n = 25）1）,2）

Baseline
6‑week⊿ 0‑6 w

26.5 ± 2.0
26.9 ± 2.3
0.4 ± 2.4

26.7 ± 2.2
27.3 ± 1.6
0.6 ± 2.5

26.6 ± 2.7
27.8 ± 2.2 ＊1.2 ± 2.2

12‑week⊿ 0‑12 w

28.1 ± 1.8 ＊＊1.6 ± 2.4

28.3 ± 1.7 ＊＊1.7 ± 2.2

27.7 ± 2.5
1.1 ± 3.5

Baseline
6‑week⊿ 0‑6 w

4.4 ± 1.6
4.8 ± 1.3
0.3 ± 1.8

4.0 ± 1.8
4.5 ± 1.3
0.4 ± 1.6

4.0 ± 1.5
4.0 ± 1.6 ‡0.0 ± 1.6

12‑week⊿ 0‑12 w

4.6 ± 1.4
0.1 ± 2.1

4.3 ± 1.6
0.3 ± 1.5

4.2 ± 1.5
0.2 ± 1.7

Values are expressed as the mean±SD.
1）* :p < 0.05, ** :p < 0.01 against baseline.
2）‡ :p < 0.1 between-group diﬀerence in Test-1 versus Placebo.

(supplement) containing plasmalogen. The objective of
this study was to verify whether the supplement
containing plasmalogen aﬀects the memory skill and thecognitive capacity of a healthy human. The study adapted
two types of test method: the test using the test productcontaining 0.5 mg of plasmalogen (Test 1) and 0.25 mg ofplasmalogen (Test 2), and both tests applied placebocontrolled group for comparison.
As the primary outcome, the two test groups bothshowed significant differences in the results of MMSE
after 12-week ingestion, compared to Placebo. The
results of U-K test, on the other hand, did not show
signiﬁcant diﬀerences in any groups. As for the subjective
reporting of the cognitive function in the form of aquestionnaire, intragroup analysis of the test productshowed significant differences in more than half of theitems, whereas inter-group analysis between the test
group (Test 2) and the Placebo group showed increases

diﬀerences in 4 to 14 items. In addition, as the secondary
outcome, no adverse effects associated with the test
product were observed in the course of the reporting,and the safety of ingesting the test product wasestablished.
Main Findings
In the results of MMSE, significant increases wereobserved in the intragroup analysis of Test-1 (0.5 mg)
a n d Te s t - 2 ( 0 . 2 5 m g ) a f t e r 1 2 - w e e k i n g e s t i o n ,respectively. MMSE is the examination which is widelyused for testing the cognitive function. Although its main
purpose is to screen dementia by measuring the cognitive
function, this examination can be also applied to healthy
humans who want to verify the decline of their cognitive
function 8). As for the results of U-K test, on the other
hand, no significant difference was observed in theintragroup analysis of Test-1, Test-2, and Placebo.
Kraepelin test can evaluate not only one s intelligence or44 （1130）

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Table 5

第 12 号（2016 年 12 月）

Results of questionnaire analyses (1)Scores

No.

1

2

3

4

5

6

7

8

9

Time point

Test-1（0.5 mg）

Test-2（0.25 mg）

Placebo（n = 27）1）

1）（n = 23）（n = 25）2）3）

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.4 ± 0.8 ＊＊2.2 ± 0.4 ＊2.0 ± 0.5

⊿ 0‑6 w

0.4 ± 0.8

0.2 ± 0.4

0.0 ± 0.5 b, e＊＊＊

12‑week

2.6 ± 0.8

⊿ 0‑12 w

0.6 ± 0.8

0.3 ± 0.6

0.0 ± 0.5 c

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.2 ± 0.6

2.1 ± 0.5

2.0 ± 0.5

⊿ 0‑6 w

0.2 ± 0.6

0.1 ± 0.5＊＊

2.3 ± 0.6

2.0 ± 0.5

0.0 ± 0.5＊＊

12‑week

2.5 ± 0.8

⊿ 0‑12 w

0.5 ± 0.8

0.5 ± 0.5

0.0 ± 0.7 b, eBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.2 ± 0.6

2.1 ± 0.3

2.2 ± 0.4 ＊⊿ 0‑6 w

0.2 ± 0.6

2.5 ± 0.5

0.2 ± 0.4

0.1 ± 0.3＊＊

2.0 ± 0.7＊

2.4 ± 0.6 ＊＊12‑week

2.4 ± 0.7

⊿ 0‑12 w

0.4 ± 0.7

0.3 ± 0.5

0.4 ± 0.6 dBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.2 ± 0.6 †2.3 ± 0.5 ＊＊2.0 ± 0.6

⊿ 0‑6 w

0.2 ± 0.6

0.3 ± 0.5

0.0 ± 0.6＊＊

2.3 ± 0.5＊＊

2.2 ± 0.5 †12‑week

2.5 ± 0.6

⊿ 0‑12 w

0.5 ± 0.6

0.5 ± 0.5

0.2 ± 0.5 b, eBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.4 ± 0.6 ＊＊2.4 ± 0.6 ＊＊1.8 ± 0.6 †0.4 ± 0.6##

− 0.2 ± 0.6 c

2.5 ± 0.6＊＊

1.8 ± 0.6 †⊿ 0‑6 w

0.4 ± 0.6＊＊

2.5 ± 0.5

12‑week

2.6 ± 0.6

⊿ 0‑12 w

0.6 ± 0.6

0.5 ± 0.6

− 0.2 ± 0.6 c, fBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.4 ± 0.7 ＊＊2.2 ± 0.5 †2.3 ± 0.5 ＊＊⊿ 0‑6 w

0.4 ± 0.7

0.2 ± 0.5

0.3 ± 0.5＊＊＊

12‑week

2.4 ± 0.8

⊿ 0‑12 w

0.4 ± 0.8

0.3 ± 0.4

0.1 ± 0.4 aBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.3 ± 0.8 ＊2.2 ± 0.4 ＊2.0 ± 0.0

⊿ 0‑6 w

0.3 ± 0.8

0.2 ± 0.4

0.0 ± 0.0 b, e

12‑week

2.4 ± 0.8 ＊＊2.2 ± 0.5 †2.2 ± 0.4 ＊⊿ 0‑12 w

0.4 ± 0.8

0.2 ± 0.5

0.2 ± 0.4

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.4 ± 0.8 ＊＊2.1 ± 0.5

2.0 ± 0.2

⊿ 0‑6 w

0.4 ± 0.8

0.1 ± 0.5

0.0 ± 0.2 b

12‑week

2.5 ± 0.8 ＊＊2.3 ± 0.5 ＊2.0 ± 0.0

⊿ 0‑12 w

0.5 ± 0.8

0.3 ± 0.5

0.0 ± 0.0 c, eBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.1 ± 0.8

2.1 ± 0.3

2.0 ± 0.5

⊿ 0‑6 w

0.1 ± 0.8

0.1 ± 0.3

0.0 ± 0.5

12‑week

2.4 ± 0.7 ＊2.4 ± 0.5 ＊＊2.1 ± 0.4

⊿ 0‑12 w

0.4 ± 0.7

0.4 ± 0.5

0.1 ± 0.4 d

2.3 ± 0.4

2.1 ± 0.4

Scores are expressed as the mean ± SD.
1）†:p < 0.1, * :p <0.05, ** :p < 0.01 against baseline.
2）b :p < 0.05, c :p <0.01 between-group diﬀerences in Test-1 versus Placebo.
3）d :p < 0.1, e :p <0.05, f :p < 0.01 between-group diﬀerences in Test-2 versus Placebo.

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第 12 号（2016 年 12 月）

Table 5 Results of questionnaire analyses (2)Scores
No.

10

11

12

13

14

15

16

17

18

Time point

Test-1（0.5 mg）

Test-2（0.25 mg）

Placebo（n = 27）1）

1）（n = 23）（n = 25）2）3）

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.3 ± 0.6 ＊2.2 ± 0.4 ＊2.0 ± 0.2

⊿ 0‑6 w

0.3 ± 0.6

0.2 ± 0.4

0.0 ± 0.2 a, d＊＊＊＊

2.2 ± 0.4 ＊12‑week

2.4 ± 0.7

⊿ 0‑12 w

0.4 ± 0.7

0.4 ± 0.6

0.2 ± 0.4

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

1.9 ± 0.6

2.2 ± 0.4 ＊2.0 ± 0.4

⊿ 0‑6 w

− 0.1 ± 0.6

0.2 ± 0.4

0.0 ± 0.4 d

2.4 ± 0.6

12‑week

2.1 ± 0.4

2.3 ± 0.5 ＊2.1 ± 0.3 †⊿ 0‑12 w

0.1 ± 0.4

0.3 ± 0.5

0.1 ± 0.3

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.3 ± 0.6 ＊＊2.3 ± 0.4 ＊2.0 ± 0.4

⊿ 0‑6 w

0.3 ± 0.6

0.3 ± 0.4

0.0 ± 0.4 b, d

12‑week

2.4 ± 0.5 ＊＊2.3 ± 0.5 ＊2.0 ± 0.4

⊿ 0‑12 w

0.4 ± 0.5

0.3 ± 0.5

0.0 ± 0.4 c, dBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.3 ± 0.5 ＊2.2 ± 0.4 ＊2.0 ± 0.3

⊿ 0‑6 w

0.3 ± 0.5

0.2 ± 0.4

0.0 ± 0.3 b, d

12‑week

2.2 ± 0.5 ＊2.2 ± 0.4 ＊2.0 ± 0.5

⊿ 0‑12 w

0.2 ± 0.5

0.2 ± 0.4

0.0 ± 0.5

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.1 ± 0.6

2.3 ± 0.6 ＊＊2.0 ± 0.5

⊿ 0‑6 w

0.1 ± 0.6

0.3 ± 0.6

0.0 ± 0.5 d†＊＊

2.2 ± 0.4 ＊12‑week

2.2 ± 0.6

⊿ 0‑12 w

0.2 ± 0.6

0.4 ± 0.6

0.2 ± 0.4

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.1 ± 0.7

2.3 ± 0.5 ＊＊2.1 ± 0.6

⊿ 0‑6 w

0.1 ± 0.7

0.3 ± 0.5

0.1 ± 0.6 d

12‑week

2.2 ± 0.6

2.4 ± 0.5 ＊＊2.0 ± 0.5

⊿ 0‑12 w

0.2 ± 0.6

0.4 ± 0.5

0.0 ± 0.5 f

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.3 ± 0.6 ＊＊2.3 ± 0.5 ＊＊2.1 ± 0.3 †⊿ 0‑6 w

0.3 ± 0.6

0.3 ± 0.5

0.1 ± 0.3＊

2.4 ± 0.6＊＊

2.1 ± 0.3

12‑week

2.4 ± 0.8

⊿ 0‑12 w

0.4 ± 0.8

0.7 ± 0.6

0.1 ± 0.3 a, fBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.3 ± 0.7 ＊2.3 ± 0.5 ＊＊1.9 ± 0.5

⊿ 0‑6 w

0.3 ± 0.7

0.3 ± 0.5

− 0.1 ± 0.5 b, f

12‑week

2.4 ± 0.9 ＊2.4 ± 0.5 ＊＊2.1 ± 0.4

⊿ 0‑12 w

0.4 ± 0.9

0.4 ± 0.5

0.1 ± 0.4 e

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.3 ± 0.5 ＊＊2.0 ± 0.4

2.0 ± 0.3

⊿ 0‑6 w

0.3 ± 0.5

0.0 ± 0.4

0.0 ± 0.3 b

2.1 ± 0.4

2.2 ± 0.4 ＊0.1 ± 0.4

0.2 ± 0.4

12‑week

2.4 ± 0.8

⊿ 0‑12 w

0.4 ± 0.8＊

2.7 ± 0.6

Scores are expressed as the mean ± SD.
1）†:p < 0.1, * :p < 0.05, ** :p < 0.01 against baseline.
2）a :p < 0.1, b :p < 0.05, c :p < 0 .01 between-group diﬀerences in Test-1 versus Placebo.
3）d :p < 0.1, e :p < 0.05, f :p < 0.01 between-group diﬀerences in Test-2 versus Placebo.

46 （1132）

診療と新薬・第 53 巻

第 12 号（2016 年 12 月）

Table 5 Results of questionnaire analyses (3)Scores
No.

19

20

21

22

23

24

25

26

27

Time point

Test-1（0.5 mg）

Test-2（0.25 mg）

Placebo（n = 27）1）

1）（n = 23）（n = 25）2）3）

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.2 ± 0.6

2.1 ± 0.3

2.0 ± 0.5

⊿ 0‑6 w

0.2 ± 0.6

0.1 ± 0.3

0.0 ± 0.5

12‑week

2.4 ± 0.6

2.3 ± 0.6 ＊＊2.2 ± 0.5 †⊿ 0‑12 w

0.4 ± 0.6

0.3 ± 0.6

0.2 ± 0.5

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.3 ± 0.7 †2.1 ± 0.5

2.1 ± 0.3

⊿ 0‑6 w

0.3 ± 0.7

0.1 ± 0.5＊

0.1 ± 0.3＊＊

12‑week

2.3 ± 0.7

⊿ 0‑12 w

0.3 ± 0.7

0.4 ± 0.5

0.0 ± 0.4 a, fBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.3 ± 0.7 ＊2.3 ± 0.4 ＊2.1 ± 0.5

⊿ 0‑6 w

0.3 ± 0.7

0.3 ± 0.4

0.1 ± 0.5

2.4 ± 0.5＊＊＊

2.0 ± 0.4

12‑week

2.3 ± 0.7

⊿ 0‑12 w

0.3 ± 0.7

0.6 ± 0.7

0.1 ± 0.4 f

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.2 ± 0.6 †2.2 ± 0.5 †2.0 ± 0.4

⊿ 0‑6 w

0.2 ± 0.6

0.2 ± 0.5

0.0 ± 0.4

2.6 ± 0.7＊＊＊

2.1 ± 0.4

12‑week

2.4 ± 0.7

⊿ 0‑12 w

0.4 ± 0.7

0.2 ± 0.4

0.1 ± 0.3

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.2 ± 0.6 †2.1 ± 0.3 †2.0 ± 0.5

⊿ 0‑6 w

0.2 ± 0.6

0.1 ± 0.3

0.0 ± 0.5

12‑week

2.3 ± 0.8 †2.7 ± 0.7 ＊＊2.2 ± 0.4 ＊⊿ 0‑12 w

0.3 ± 0.8

0.7 ± 0.7

0.2 ± 0.4 f

Baseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.2 ± 0.8

2.1 ± 0.3 †1.9 ± 0.4

⊿ 0‑6 w

0.2 ± 0.8

0.1 ± 0.3

− 0.1 ± 0.4 d

12‑week

2.3 ± 0.8 ＊2.5 ± 0.7 ＊＊1.8 ± 0.5

⊿ 0‑12 w

0.3 ± 0.8

0.5 ± 0.7

− 0.2 ± 0.5 b, fBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.4 ± 0.7 ＊＊2.2 ± 0.4 ＊2.1 ± 0.3

⊿ 0‑6 w

0.4 ± 0.7

0.2 ± 0.4

0.1 ± 0.3 b

12‑week

2.4 ± 0.7 ＊2.4 ± 0.5 ＊＊2.2 ± 0.4 ＊⊿ 0‑12 w

0.4 ± 0.7

0.4 ± 0.5

0.2 ± 0.4 dBaseline

2.0 ± 0.0

2.0 ± 0.0

2.0 ± 0.0

6‑week

2.2 ± 0.7

2.3 ± 0.6 ＊2.0 ± 0.2

⊿ 0‑6 w

0.2 ± 0.7

0.3 ± 0.6

0.0 ± 0.2 e

12‑week

2.3 ± 0.8

2.6 ± 0.7 ＊＊2.1 ± 0.3

⊿ 0‑12 w

0.3 ± 0.8

0.6 ± 0.7

0.1 ± 0.3 f

Baseline

52.0 ± 0.0

52.0 ± 0.0

52.0 ± 0.0

6‑week

58.6 ± 12.0 ＊＊57.5 ± 6.5 ＊＊52.7 ± 4.3⊿ 0‑6 w

6.6 ± 12.0

5.5 ± 6.5

0.7 ± 4.3 b, f

12‑week61.7 ± 15.8

⊿ 0‑12 w

9.7 ± 15.8＊＊

2.2 ± 0.4

62.0 ± 7.9
10.0 ± 7.9＊＊

2.1 ± 0.3

54.4 ± 3.7 ＊＊2.4 ± 3.7 b, f

Scores are expressed as the mean ± SD.
1）†:p < 0.1, * :p < 0.05, ** :p < 0.01 against baseline.
2）a :p < 0.1, b :p < 0.05 between-group diﬀerences in Test-1 versus Placebo.
3）d :p < 0.1, e :p < 0.05, f :p < 0.01 between-group diﬀerences in Test-2 versus Placebo.

診療と新薬・第 53 巻

working property but also one s mental health, by doing asimple addition continuously 9). Regarding the subjective
reporting of the cognitive function using a questionnaire,the intragroup analysis of both Test-1 (0.5 mg) and Test2 (0,25 mg) showed significant differences in more thanhalf of the items. Also in the intergroup analysis, Test-1
group showed signiﬁcant improvement in 10 items after
6-week ingestion, while Test-2 group showed signiﬁcant
improvement in 14 items after 12-week ingestion,compared to Placebo. In addition, in the total score there
was significant difference in all the groups (including
Placebo), compared to the baseline. The questionnaire
items about the cognitive function were all prepared by
the test doctor in charge of this study, and these items
were designed to judge the decline of cognitive function
or life function. This questionnaire is also based on theknowledge of Tokyo Metropolitan Institute ofGerontology10). In this questionnaire, signiﬁcant diﬀerence
was mainly found in the items related to living functions
such as language, position or situation. There were also a
lot of items showing signiﬁcant diﬀerence in the Placebo.
Based on the above, regarding the ingestion of the test
product even though in the Kraepelin test, which adopts
the calculation-task as its evaluation instrument, we
could not observe any signiﬁcant diﬀerence, in the othertests we could observe the improvements of somecognitive functions related to the memory of information.
Plasmalogens contained in the test product of thisstudy are a unique subclass of glycerophospholipids
characterized by the presence of a vinyl ether bond at thesn-1 position of the glycerol backbone, and they are foundin high concentration in cellular membranes of many
mammalian tissues. On the other hand, the human brain
consists of three parts: the brain stem controlling thebasic function for living, the limbic system with functions
such as a primitive instinct, an emotion and memory, andthe cerebral cortex that takes care of advanced activities.
The hippocampus, which controls memory, is located in
the cerebral limbic system. New information is once ﬁled
by the hippocampus (short-term storage). Then, theinformation is stored in the cerebral cortex if the
hippocampus recognizes it as necessary (long-term
storage). The hippocampus is very fragile and delicate,and once it becomes dysfunctional, we cannot remember
something new. Also, the damage of the brain caused by
insuﬃcient oxygen starts from that of the hippocampus.
In addition, it is believed that diseases such as
posttraumatic stress disorder or Alzheimer dementia are
triggered as a result of the disorder of the
hippocampus 11)12). The decline of cognitive function isthought to be induced by the damage of the hippocampusby oxidant stress or the accumulation of amyloid βprotein13).
Several reports indicate that there is a paucity ofplasmalogen in the brain of patients with Alzheimer sdisease 14)15) , and this supports the hypothesis that

第 12 号（2016 年 12 月）

47（1133）

plasmalogen is related to the cognitive function. It isreported that plasmalogen inhibits neuronal cell death(apoptosis) by enhancing the activation of protein kinasesuch as Akt (protein kinase B) or ERK (Extracellularsignal-Regulated Kinase) 16). Another report indicates thatplasmalogen has the promotive effect of neurogenesis,
the anti-neuroinﬂammatory eﬀect and anti-amyloidogenic
effect of amyloid β 17) . It is reported that the oral
administration of plasmalogen increases the level oferythrocyte ethanolamine plasmalogen18). Based on these
discussions, it can be speculated that the oral
administration of plasmalogen contributes to theimprovement of the cognitive function, which is causedby the increase of the level of erythrocyte ethanolamine
plasmalogen, the activation of protein kinase, theinhibition of production/accumulation of amyloid β andthe promotion of neurogenesis of hippocampus19). On theother hand, the abilities required for the Kraepelin test
involve not only the short-term memory controlled byhippocampus but also the complex functions such asconcentration or calculation, which require theinvolvement of other parts of brain20). The results of thequestionnaire conducted in this study tended not to show
signiﬁcant improvement in the items other than those oflanguage, position or situation, which require functions
other than memory. Therefore, it can be said that theoral administration of plasmalogen is effective for the
improvement of the cognitive function as explained
above, while it does not contribute to the rather complex
functions the other parts of brain mutually involve.
Secondary Findings
In this study, adverse events were collected by means ofa written questionnaire during the study, and noabnormal change caused by the test product wasobserved during the ingesting period. During the test
period six test subjects discontinued the test. The
reasons of discontinuance were personal ones such as
illness (catching a cold) or work, and it has nothing to dowith the ingestion of the test product. These results
indicated the safety of the ingestion of the test productfor the 12-week test period.
General Information
In the present Japanese aging society, the number of both
outpatients and inpatients with dementia is increasing.
Also, facts such as the increase in the number of carereceivers, the falling birth rate and the trend toward
nuclear families all trigger an increase of the caregiverburden, and they eventually lessen the quality of acaregiver s life remarkably. These phenomena are now
regarded as a serious social problem 21). The symptom of
dementia gets worse and worse with the lapse of timesince it is a progressive brain disorder 22)23). Therefore, it
is critical to consider how to prevent dementia. The
plasmalogen used in this study restrains the accumulationof amyloid βwhich is believed as the causative agent ofdementia 24), and this fact supports the hypothesis that it

48 （1134）

診療と新薬・第 53 巻

is also effective for the prevention of dementia. Also,
Researchers have well established that a variety ofcognitive abilities including memory, processing speed,
and problem solving, decline with increasing age 25).
Therefore it is reasonable to consider that the
improvement of the cognitive function significantly
relates to the improvement of quality of life (QOL) 26).
Based upon the above discussion, it is contemplated thatthe ingestion of the food of supplement type (which iseasily prepared) contributes to allowing the elderly to
become more active in life.
Limitations
In this study we veriﬁed the cognitive function of human.
Since the cognitive function is a feature of the brain, it
can be inﬂuenced by the consciousness or the feelings ofthe test subject. Therefore it is undeniable that the result
has some sort of bias caused by a placebo effect 27). We
observed significant improvement in some items of thequestionnaire conducted by the Placebo group, and thisresult may be a result of placebo eﬀects. Therefore, forthe analysis of the test results it is recommended toevaluate not only the subjective reporting such as aquestionnaire, but also some objective indicators as well.
In addition, it is necessary to gather the data from alarger number of test subjects, and compare the actualeﬀect and the placebo eﬀect based on it.

5. CONCLUSION
In conclusion, we found out that the ingestion of the
supplement containing plasmalogen for 12 weeks
contributed to the improvement of some cognitive
functions related to language and situation. In addition,no safety-related matter occurred during the 12-weektest period.
CONFLICT OF INTEREST
All parts of this study were funded by P-Solution Inc. Hitoshi Nagata is aprincipal. All authors state that the study was conducted in the absence of
any other relationships that could be interpreted as a conﬂict of interest.

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診療と新薬・第 53 巻
Appendix 1. Questionnaire for screening

第 12 号（2016 年 12 月）

49（1135）

Appendix 2. MMSE

The Mini-Mental State Exam
Q1. Do you feel like your becoming
forgetful recently?

Patient :̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲ Examiner :̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲̲ Date :̲̲̲̲̲̲̲̲̲̲̲
<Maximum><Score>

Orientation

1. No

2. Yes, sometime
3. Yes
4. Yes, frequency

5
5

(
(

)
)

Whatis the (year) (season) (date) (day) (month)?
Where are we (state) (country) (town) (hospital) (ﬂoor)?

3

(

)

Name 3 objects: 1 second to say each. Then ask the patient
all 3 after you have said them. Give 1 point for each correct answer.
Then repeat them until he/she learns all 3. Count trials and record.
Trials̲̲̲̲̲̲̲̲̲̲̲̲

5

(

)

Serial 7 s. 1 point for each correct answer. Stop after 5 answers.
Alternatively spell world backward.

3

(

)

Ask for the 3 objects repeated above. Give 1 point for each correct answer.

2
1
3

(
(
(

)
)
)

1
1
1

(
(
(

)
)
)

Name a pencil and watch.
Repeat the following No ifs, ands, or buts
Follow a 3-stagecommand:
Take a paper in your hand, fold it in half, and put it on the ﬂoor.
Read and obey the following: CLOSE YOUR EYES
Write a sentence.
Copy the design shown.

Registration

EliminatedQ2. Canyou recall quickly what
you had for lunch yesterday?

Attention and Calculation

Recall
1. Yes

2. Yes, but it takes a little bit
3. Yes, but it takes a lot
4. No

EliminatedQ3. Do you ﬁnd troublesome toremember things?

1. No

Language

2. Yes, a little bit
3. Yes
4. Yes, deﬁnitely

Total score :̲̲̲̲̲̲̲̲̲̲̲

EliminatedRandomized

Interpretation: 24-30; No cognitive impairment, 18-23; Mild cognitive impairment, 0-17; Severe
cognitive impairment

Appendix 3 . Questionnaire of subjective reporting
Scale of 0 to 4, with 2 representing the baseline status, with higher scoresindicating a better result.
Question #1: Do you know the date?
Question #2: Can you get to a place where you have been before?
Question #3: Can you remember your address and phone number?
Question #4: Can you remember the place where you leave things?
Question #5: If an item is not in its usual place, can you ﬁnd it easily?
Question #6: Can you manage the use of your TV, washing machine,
remote, etc.?
Question #7: Can you select cloths according to situation?
Question #8: When buying something, can you pay the correct amount in
cash?
Question #9: Despite being healthy, do you feel lack of motivation for
activities?
Question #10: Can you fully understand the contents of a book or TV
program?
Question #11: Do you write letters?
Question #12: Can you remember what you talked about with someone a
few days prior?

Question #13: Do you ﬁnd it troublesome recalling a conversation a few
days ago without someone s help?
Question #14: Whilst having a conversation, do you forget things you
want to say?
Question #15: Whilst having a conversation, do you forget easy
vocabulary?
Question #16: Can you recognize the face of people you know?
Question #17: Can you remember the name of people you know?
Question #18: Can you recall where those people live and work?
Question #19: Do you become forgetful even regarding recent things?
Question #20: During a short time, do you repeat things you say or ask?
Question #21: Do you often misplace, or forget to leave things behind?
Question #22: Do you miss or become late for appointments due toproblems of recalling details?
Question #23: Do you often make mistakes on calculations?
Question #24: Do you get lost in familiar places?
Question #25: Do you ﬁnd yourself forgetting to turn oﬀ the tap or gas
after using it?
Question #26: Can you easily urinate? Do you urinate frequently?
Sometimes do you experience leakage?
Question #27: Overall