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J. Clin. Biochem. Nutr., 47, 246–255, November 2010 Advance Publication istry and Nutriti cal Research Japanon Soybean-Derived Phosphatidylserine Improves Memory Function of the Elderly Japanese Subjects with Memory Complaints Akito Kato-Kataoka1,*, Masashi Sakai1, Rika Ebina1, Chiaki Nonaka2, Tsuguyoshi Asano3 and Takashi Miyamori4 1Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi, Tokyo 186-8650, Japan2Development Dept., Yakult Honsha Co., Ltd., 1-1-19 Higashi-Shimbashi, Minato, Tokyo 105-8660, Japan3Asano Institute of Preventive Medicine, 1-18-3 Higashi-Kanamachi, Katsushika, Tokyo 125-0041, Japan4Graduate School of Clinical Psychology, Tokai University, 1117 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan ; accepted 1.6.201 Received 11 June, 2010; Accepted 14 July, 2010; Published online 29 September, 2010 bean-derived phosphatidylserine (Soy-PS) is a phosphatidylserine made from soybean lecithin by enzymatic reaction with L-serine. A double-blind, randomized controlledstudy was conducted to investigate the effects of Soy-PS on the cognitive functions of the elderlyJapanese subjects with memory complaints. Seventy-eight elderly people with mild cognitiveimpairment (50–69 years old) were randomly allocated to take Soy-PS (100 mg, 300 mg/day)or placebo for 6 months. As a result, there was no difference in blood markers and vital signsduring Soy-PS treatment and any side effect caused by Soy-PS treatment was not observed.
Neuropsychological test scores were similarly increased in all groups including placebo group.
However, in the subjects with relatively low score at baseline, the memory scores in PS treatedgroups were significantly increased against the baseline, while those of placebo groupremained unchanged. And the memory improvements in Soy-PS-treated groups were mostlyattributed to the increase in delayed verbal recall, a memory ability attenuated in the earlieststage of dementia. In conclusion, Soy-PS used in this study is considered as safety foodingredient and 6 months of Soy-PS supplementation could improve the memory functions ofthe elderly with memory complaints.
Key Words: phosphatidylserine, soybean, elderly, memory functions, delayed verbal recall associated memory impairment (AAMI) [10]. However, the use of BC-PS in medicine or dietary supplements is nowdiscouraged because of the risk of bovine spongiform Phosphatidylserine (PS) is a member of the membrane encephalopathy (BSE) [11]. In addition, only about 3 grams phospholipids that is especially abundant in the brain.
of PS can be obtained from one bovine cortex, which is too Because of its presence in the brain, effects of PS on the small for inexpensive supply.
central nervous system have been widely investigated [1–5].
Efforts to overcome these problems have led to the Several clinical studies in the US and Europe have shown development of soybean-derived PS (Soy-PS), a BSE risk- that PS extracted from bovine cortex (BC-PS) improves free PS that is enzymatically made from soybean lecithin the cognitive function of the elderly [6–10] including [12]. Even though the acyl-groups of Soy-PS are quite Alzheimer's disease patients [8, 9] and people with age- different from that of BC-PS, studies using drug-inducedamnesic and aged rodents have suggested that the effects ofSoy-PS on cognitive function are identical to that of BC-PS *To whom correspondence should be addressed. Tel: +81-42-577-8960 Fax: +81-42-577-3020 However, the results of clinical studies using Soy-PS are Effects of Soybean Phosphatidylserine on Memory Functions controversial. In 1995, Gindin et al. [17] first reported a complaints were recruited from the volunteer bank of clinical study of Soy-PS, where Soy-PS treatment (300 mg/ clinical research organization (Huma R&D Co. Ltd., Tokyo).
day for 3 months) on elderly people with AAMI improved Prior to the screening with neuropsychological tests, a their Wechsler Memory test scores, especially in the compo- preliminary assessment was conducted at the recruiting nents of the test that evaluated visual memory. In their study, process to evaluate objective memory loss. Specifically, the effect of Soy-PS was evident only in the subgroup of the DWR subtest of HDS-R was done over the phone, and subjects that had higher pre-treatment scores. Crook et al.
those with 3 to 5 points out of 6 were selected. For further [18] reported that Soy-PS (300 mg/day for 12 weeks) screening, people who passed this preliminary assessment was effective in improving memory functions, such as took part in three neuropsychological tests (RBMT, HDS-R memorizing names and faces, of elderly people with AAMI.
and Mini-Mental State Examination: MMSE [23]) and a Schreiber et al. [19] also reported similar results that Soy-PS medical interview, and those who fulfilled the selection was most effective on memorizing faces.
criteria became the subjects for this clinical study.
Jorissen et al. [20] performed a double-blind placebo- To screen out people with severe cognitive disorder who controlled study to evaluate the efficacy of two different need medical treatment, the selection criteria were set so as doses of Soy-PS (300 or 600 mg/day for 12 weeks) on the to include people with mild memory impairment (RBMT elderly with AAMI. Although various aspects of cognitive standard profile score<22) while excluding those with function including memory, information processing speed, possible dementia (HDS-R<21, MMSE<24).
selective attention and planning were measured, no difference Procedures for this study were approved by the institu- was found between placebo and Soy-PS treated groups even tional review board of the testing agency, Tokyo Heart with the higher dosage. Thus, it is still controversial whether Center (Tokyo, Japan). All subjects gave a written informed Soy-PS is effective for the elderly with memory impairment.
consent before entering the study.
Furthermore, there has been no clinical study that evaluates In total, 143 out of approximately 700 volunteers passed the effects of PS on memory impairment using Japanese the preliminary assessment on the phone, and 78 of them fulfilled the selection criteria. Out of 78 subjects who To clarify whether Soy-PS is beneficial for cognitive entered the study, 73 completed the study and 5 dropped out function of the elderly, we conducted a preliminarily open- (n = 3 in placebo, n = 1 in 100 mg Soy-PS and n = 1 in trial test in 2005 and found that 12 weeks of Soy-PS treat- 300 mg Soy-PS). The reasons for dropout were either private ment (300 mg/day) on elderly people with mild memory circumstances or health problems not related to PS treat- impairment improved their scores on the revised version of ment. The design of this study and trial profile are shown in Hasegawa's dementia scale (HDS-R) [21], a general test used for diagnosis of dementia in Japan. Improvement wasespecially evident in the delayed 3 words recall (DWR) subtest. In addition, the effect of Soy-PS on DWR was The study was designed as a randomized, double-blind, maintained for 12 weeks after the treatment period was placebo-controlled, parallel-group trial. The subjects were over. Based on these results, we next planned a double-blind, randomly divided into three groups (n = 28 in each group), placebo-controlled clinical study.
all similar in average age, sex, education year, neuro- The present study was designed as a double-blind, placebo- psychological test score, geriatric depression scale (GDS) controlled trial to evaluate the efficacy of Soy-PS (100 mg [24] score and everyday memory checklist (EMC) score or 300 mg/day for 6 months) on the Japanese elderly with (Tables 1 and 5).
mild memory impairment. For the selection of subjects Within one month after the screening session, subjects with mild memory impairment, we used the Rivermead started taking their respective test samples: placebo, 100 mg behavioral memory test (RBMT) [22], which focuses on Soy-PS (PS100) or 300 mg Soy-PS (PS300), daily for 6 evaluating memory functions, especially everyday memory.
months. Six months of PS treatment was followed by a 3- The treatment period of Soy-PS was set to 6 months, with month follow-up period during which subjects took no an additional 3-month follow-up period to see whether the samples. For all measurements, the screening values were effects of Soy-PS would be maintained after discontinuing used as baseline values.
The following examinations were conducted at baseline, after 6 months of PS treatment and after 3 months of follow- Materials and Methods up period: HDS-R and MMSE for evaluating cognitivefunction, GDS for evaluating depressive state, and blood/ urine tests for evaluating safety. In addition, RBMT and Men and women living in the Tokyo metropolitan area, EMC were conducted at baseline, at 1, 3 and 6 months of ranging from 50 to 69 years old, with subjective memory PS treatment and after 3 months of follow-up.
Vol. 47, No. 3, 2010 A. Kato-Kataoka et al.
The study design and trial profile.
Baseline characteristics of each treatment group phospholipids other than PS (PL), 702 mg middle-chaintriglycerides (MCT) and 135 mg vitamin E (VE). Nine capsules of PS100 contained 100 mg PS, 863 mg PL, Number of subjects 702 mg MCT and 135 mg VE. Nine capsules of placebo contained 963 mg PL, 702 mg MCT and 135 mg VE.
To prevent degradation of Soy-PS, a portion of the test samples was sent to the subjects every month and was keptunder refrigeration at home.
Values are mean ± SEM. The subjects in PS100 and PS300 groups took 100 mg/d and 300 mg/d of Soy-PS for 6 months, respectively.
Primary outcome measures were cognitive functions Placebo group took soybean lecithin containing no PS.
assessed by HDS-R, MMSE and RBMT. Secondary out-comes were self-rating memory function assessed by EMC and depressive state assessed by GDS. Blood and urine Food-grade Soy-PS product (PS-20L, Yakult Honsha Co.
parameters were also assessed for safety evaluation.
Ltd., Japan) produced from soybean lecithin by enzymatictransphosphatidylation reaction was used in this study [25].
Test samples were taken in the form of soft gelatin capsules RBMT is a standardized and validated test for memory (200 mg of content per capsule). Subjects took 3 capsules functions [22]. It consists of 12 subtests for evaluating after each meal, a total of 9 capsules per day, for 6 months.
everyday memory such as of personal event, people's The timing of Soy-PS intake was decided according to names, newspaper articles and places visited. The Japanese previous papers [19, 20].
version of RBMT was developed by Kazui et al. [26] in Nine capsules of PS300 contained 300 mg PS, 663 mg 2002. Standardized profile score is obtained by assigning a J. Clin. Biochem. Nutr.
Effects of Soybean Phosphatidylserine on Memory Functions score of 0, 1, or 2 to each of the 12 subtests, summing up to cation criteria. Regarding stratified analyses, changes in a maximum total score of 24 points. Degree of memory score against the baseline were used in order to correct for impairment is categorized into 4 classes according to the initial differences among the groups. SAS 8.2 for Windows standardized profile score; 0–9: severely impaired, 10–16: was used for statistical analyses, with significance set at moderately impaired, 18–21: poor memory, >21: normal.
Four parallel forms (A, B, C and D) of the test were used in Safety of Soy-PS was evaluated by the deviation from the the present study to avoid practice or learning effects.
normal range of blood and urine parameters, and its clinicalsignificance was judged by a physician.
HDS-R is a neuropsychological battery commonly used for diagnosis of dementia in Japan [27], along with MMSE.
Those who score less than 21 points out of 30 are diagnosed as "possible dementia". The test assesses orientation, Throughout the test period, no adverse event was observed memory, attention and verbal fluency. We especially focused in relation to sample intake. There was also no clinically on the DWR subtest, because Soy-PS was most effective significant change in hematological and biological blood on that subtest in our preliminary study [21]. In DWR, a parameters in all groups (Tables 2 and 3). Although a subject is presented with 3 unrelated words and is later asked significant difference in blood glucose level at 6 month to recall them. For each word, the subject is given 2 points between placebo and PS100 group appeared, such difference for voluntarily recalling the word, and 1 point for recalling was not observed at higher dose (PS300) and therefore it is the word with a hint (e.g. "vehicle" for the word "car" or considered clinically insignificant. Vital signs (Table 4) and "animal" for the word "dog"). Two lists of 3 words were urine parameters (glucose, protein, occult blood and pH; prepared and the list was alternately used in this study to data not shown) didn't show any significant changes.
minimize practice effect.
Cognitive functions Table 5 shows the score changes in RBMT. The scores EMC is a questionnaire developed together with RBMT significantly increased against the baseline in all 3 groups, for evaluating difficulties in daily life caused by memory with no difference between Soy-PS and placebo groups at impairment [28]. It consists of a list of 13 memory problems any evaluation point. In stratified analysis based on the or difficult situations that likely happen in daily life.
subjects' degree of memory impairment at baseline, there Occurrence of each problem or situation is rated from 0 was still no difference between placebo and Soy-PS groups (none) to 3 (always), with a maximum score of 39 points.
either in the high-score subgroup (RBMT = 19 or more) orthe low-score subgroup (RBMT<19) (data not shown).
The total score of HDS-R increased during the treatment Medical interview by a physician was conducted at every period in all 3 groups, with no significant difference among evaluation point. Blood and urine tests were done at the groups (Table 5). However, after the 3-month follow-up baseline, end of PS treatment (6 months) and 3 months period, the score of the placebo group dropped back to its after the end of treatment. Blood pressure and heart rate baseline score, while the scores of 100PS and 300PS groups were also measured as vital signs.
were both maintained at a high level.
In the high-score subgroup, there was almost no score change in the total score of HDS-R throughout the trial Data analyses were conducted according to the protocol (Fig. 2(A)). In contrast, total score of HDS-R in the low-score for statistical analysis pre-determined before key-opening.
subgroup significantly increased against the baseline by Neuropsychological tests, EMC and GDS scores were Soy-PS treatment (Fig. 2(B)). There was a significant differ- analyzed by Steel's multi-comparison test against the base- ence between placebo and 300PS groups after 3 months of line score (within group) or against placebo (between follow-up (p<0.05). The difference between placebo and groups). Blood parameters and vital signs were analyzed 100PS also showed a significant trend (p = 0.05).
by Dunnett's multi-comparison test against placebo group Fig. 3(A) shows the DWR score of HDS-R in the low-score for each evaluation point.
subgroup. The scores of Soy-PS treated groups increased Stratified analyses based on RBMT score at baseline significantly against the baseline, and there were significant were also conducted. Since the average score of healthy differences between placebo and both Soy-PS groups after 3 Japanese adults in their 40s and 50s is reported to be months of follow-up (p<0.05 for 300PS, p = 0.09 for 22.0 ± 2.0 points [27], the score below 1.5 standard devia- 100PS). The magnitude of the score change in DWR was tion from the average (= 19 points) was used as the stratifi- quite similar to that of total score (Fig. 2(B)). It is apparent Vol. 47, No. 3, 2010 A. Kato-Kataoka et al.
Changing in hematological blood parameters during the test period 0 month (baseline§) 6 months (treatment) 9 months (follow-up) White blood count Values are means (standard deviation). §The values at screening were used as baseline values. Subjects started taking the samples withinone month after screening. The follow-up period consisted of 3 months after finishing the 6 months of sample intake, during whichsubjects took no sample.
Changing in biological blood parameters during the test period 0 month (baseline§) 6 months (treatment) 9 months (follow-up) Alkaline phosphatase 225.7 (56.0) 212.8 (51.8) 230.1 (45.7) 228.3 (61.2) 220.6 (53.5) 214.2 (41.2) 220.2 (60.1) 218.7 (47.1) 215.4 (45.1) Lactose dehydrogenase 191.7 (39.6) 197.5 (37.0) 187.2 (23.7) 187.4 (40.9) 183.9 (24.7) 180.6 (26.0) 191.5 (41.9) 193.1 (25.6) 189.1 (18.9) Creatine phosphokinase 121.6 (54.8) 166.3 (115.1) 115.3 (57.5) 125.1 (41.4) 149.8 (114.1) 116.5 (56.4) 128.2 (55.9) 175.0 (153.7) 113.5 (45.7) Blood urea nitrogen 141.0 (38.2) 128.3 (25.9) 134.3 (34.7) 130.5 (29.1) 127.7 (25.4) 142.3 (36.9) 130.9 (31.6) 126.3 (28.7) 134.2 (31.9) 89.6 (34.8) 116.1 (63.6) 121.6 (92.0) 104.7 (56.5) 113.0 (48.0) 124.0 (103.7) 99.8 (35.5) 125.7 (73.9) Values are means (standard deviation). §The values at screening were used as baseline values. Subjects started taking the samples withinone month after screening. The follow-up period consisted of 3 months after finishing the 6 months of sample intake, during whichsubjects took no sample. #p<0.05 vs placebo group (Dunnett's multi-comparison test). AST; Asparate amino transferase, ALT; Alaninetransaminase.
J. Clin. Biochem. Nutr.
Effects of Soybean Phosphatidylserine on Memory Functions Changing in vital signs during the test period 0 month (baseline§) 6 months (treatment) 9 months (follow-up) Diastolic pressure Systolic pressure Values are means (standard deviation). §The values at screening were used as baseline values. Subjects started taking the samples withinone month after screening. The follow-up period consisted of 3 months after finishing the 6 months of sample intake, during whichsubjects took no sample.
Results of the neuropsychological tests and the questionnaires of memory and mood Values are mean ± SEM. §The values at screening were used as baseline values. Subjects started taking the samples within one month afterscreening. The follow-up period consisted of 3 months after finishing the 6 months of sample intake, during which subjects took nosample. *p<0.05, **p<0.01, ***p<0.001 vs baseline, #p<0.05 vs placebo group (Steel's multi-comparison test).
that the change in total score was mainly attributed to the Subjective changes in memory and mood change in DWR subtest score. In fact, there were no signifi- Both GDS and EMC scores showed a gradual decrease in cant changes in other subtest scores of HDS-R (data not all 3 groups, but there was no significant difference among the groups at any evaluation point (Table 5).
Although the degree of change was smaller, the same trend was observed in the DWR subtest of MMSE (Fig. 3(B)).
The score significantly increased against the baseline onlyin Soy-PS treated groups, and there were significant differ- This double-blind, placebo-controlled study is the first ences between placebo and Soy-PS groups (p<0.05 for both clinical trial which demonstrates that Soy-PS has positive 100PS and 300PS). There was almost no change in other effects on cognitive performance in Japanese subjects with subtest scores of MMSE (data not shown).
memory complaints.
The effect of Soy-PS was dominant in verbal list recall tests such as the DWR of HDS-R and MMSE. This result Vol. 47, No. 3, 2010 A. Kato-Kataoka et al.
Effect of Soy-PS on DWR subtest of HDS-R and MMSE Effect of Soy-PS on HDS-R performance in high-score in the low-score subgroup (RBMT score<19 at baseline).
and low-score subgroups. Subjects were divided into (A) DWR subtest of HDS-R. (B) DWR subtest of two subgroups based on their baseline RBMT score. (A) MMSE. Values are means ± SEM and shown as changes High-score subgroup (RBMT score = 19 or more). (B) in score against the baseline. *p<0.05, **p<0.01, Low-score subgroup (RBMT score<19). Values are ***p<0.001 vs baseline, $p<0.1, #p<0.05 vs placebo means ± SEM and shown as changes in score against the group (Steel's multi-comparison test).
baseline. **p<0.01, ***p<0.001 vs baseline, $p<0.1,#p<0.05 vs placebo group (Steel's multi-comparison test).
reinforces our preliminary study in which the DWR score of demonstrated that Soy-PS is also effective on the word list HDS-R notably improved by Soy-PS treatment for 3 months recall as BC-PS.
[21]. The improving effects of PS on verbal list recall tests It has been reported that delayed verbal recall is the most have also been consistently observed in many previous effective cognitive domain for discriminating the earliest studies [29]. For example, a large clinical study of 494 stage of dementia (early Alzheimer's disease and mild elderly patients with moderate to severe cognitive decline cognitive impairment) from normal aging [30, 31]. Therefore showed that taking 300 mg of BC-PS daily for 6 months the present result that Soy-PS was effective on delayed significantly improved their performance on the word list verbal recall tests suggests that Soy-PS is effective for recall test [7]. The effect of BC-PS on list recall test was treating the earliest stage of dementia. The scores of the also observed in a study of subjects with AAMI [10]. The subtests of HDS-R and MMSE other than the verbal delayed result of our present study is well consistent with these recall were already high at baseline. Thus, Soy-PS is previous studies of BC-PS.
probably more suitable for subjects with memory complaints On the other hand, Jorissen et al. [20] reported that rather than for subjects with advanced dementia who need Soy-PS treatment was ineffective for word list recall. There medical treatment.
are differences in study design such as the selection criteria RBMT was also conducted to evaluate the effects of for subjects and the duration of treatment, and what has Soy-PS on everyday memory. RBMT includes subtests for caused the contradictory result is unclear. Nonetheless, we evaluating facial recognition and name-face association, J. Clin. Biochem. Nutr.
Effects of Soybean Phosphatidylserine on Memory Functions which have been reported to improve by PS treatment Amaducci et al., [8] who evaluated the effects of BC-PS [18, 19]. However, the effect of Soy-PS on such tests was (200 mg/day for 3 months) on the cognitive function of 142 not observed in the present study. One of the reasons may be Alzheimer's disease patients. In their study, the effect of that the subjects already marked high scores at baseline and PS was more evident after the post-treatment follow-up there was no room for further improvement. Since RBMT is period rather than immediately after 3 months of PS treat- intended for people with certain memory impairment, its ment. They proposed that PS may cause structural neuronal level of difficulty was perhaps not appropriate for the changes rather than transient metabolic changes, and subjects of this study whose memory functions were nearly therefore the beneficial effect might be maintained even after cessation of treatment.
Ceiling effects were also observed in HDS-R and MMSE.
As a supportive evidence, it has been reported that As mentioned above, the score of each subtest other than prolonged oral PS treatment elicits structural neuronal DWR was already high at baseline and there was no room changes in aged rats [36]. In summary, the dendritic spine for improvement. Consequently, the effect of Soy-PS on density of aged rats treated with BC-PS was maintained at HDS-R and MMSE was only apparent in the low-score the same level as that of young rats, whereas non-treated subgroup. The effects of Soy-PS may be observed more aged rats showed a significant decrease in dendritic density, clearly by using a more sensitive neuropsychological test with a mean loss of about 10%. It is unclear if such structural that enables the detection of subtle or mild memory impair- changes occurred in the subjects of our present study, but prolonged effects of PS have also been shown by other In this study, we tested two dosages of Soy-PS, 100 and clinical studies using BC-PS, such as in AAMI subjects [10] 300 mg/day, to determine the optimal amount of intake for and in early Alzheimer's disease patients [9].
the elderly with memory complaints. The memory-improving There is a concern that the placebo sample used in this effect of Soy-PS was equally observed in both groups.
study contained some components that have been reported to Although it is unclear whether taking 100 or 300 mg/day of have a memory-improving function, such as phosphatidyl- Soy-PS for a period of less than 6 months exerts the same choline [37], MCT [38] and VE [39]. Although the amount effect, Crook et al. [18] have reported that 100 or 300 mg/ of intake was supposedly much lower than the effective day of Soy-PS intake improved memory functions after 3 dosage of these components, there is a possibility that the weeks and 12 weeks of treatment.
placebo sample actually improved memory function by We did not measure blood PS levels in the present study, interacting synergistically and eliciting transient metabolic but some pharmacokinetics studies show that orally admin- istrated PS can be rapidly absorbed and carried to the brainthrough the blood brain barrier [32]. Our previous observa- tion that the intracerebroventricular injection of Soy-PSimproved memory impairment of amnesic mice [15] suggests The oral administration of Soy-PS for 6 months improved that Soy-PS could function in the brain directly.
memory function, especially delayed recall, in the elderly Another study has shown that the oral administration of with memory complaints. This effect was equally observed Soy-PS ameliorated the memory impairment of aged rats at both low dose (100 mg/day) and high dose (300 mg/day).
[16]. In these animals the acetylcholine release and Na+, The safety of Soy-PS was also confirmed. Since delayed K+-ATPase activity of the synaptosome were also improved.
recall is thought to be one of the cognitive functions This suggests the involvement of cholinergic transmission, impaired at the earliest stage of dementia, Soy-PS may serve energy metabolism or the status of membrane potential of as a desirable supplement for preventing dementia develop- nerve cells in the mechanism of PS action. It is also reported ment in people with memory complaints. In the future, the that PS inhibited lipid peroxidation induced by inflam- memory-improving effects of Soy-PS may be indicated matory oxidants derived from neutrophil myeloperoxidase more clearly by reconsidering the study design.
[33]. PS also decreased the production of reactive oxygenspecies from microglia induced by amyloid β peptide [34].
The anti-oxidative and/or anti-inflammatory properties ofPS may be important for its nootropic mechanism. It is We thank M. Takada and C. Takahashi for helpful assis- interesting to mention that astaxanthin, a potent antioxidant, tance during the preparation of this article.
improved delayed recall of subjects with memory complaints[35].
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