Effects of Plasmalogen on Patients with Mild Cognitive Impairment: A Randomized, Placebo-Controlled Trial in Japan
Received: 06-Jan-2018 / Accepted Date: 15-Jan-2018 / Published Date: 22-Jan-2018 DOI: 10.4172/2161-0460.1000419
Abstract
Objective: It has been shown that plasmalogens (Pls) in the brain tissue and blood decrease among Alzheimer’s disease (AD) patients. We first confirmed the effects of Pls on animal AD models, and subsequently reported that the ingestion of 1 mg Pls was effective for AD patients in a randomized, placebo-controlled trial with mild cognitive impairment (MCI) or mild AD patients. The present study examined the efficacy of orally administered Pls on patients with MCI enrolled in the previous trial in terms of individual domains of the Mini Mental State Examination-Japanese (MMSE-J).
Methods: The present analysis used 178 patients with MCI out of the 276 patients with either MCI or AD in the previously reported trial, and assessed the 24 week change in the domain-specific scores of the MMSE-J. Originally, the randomized, placebo-controlled trial was performed for 276 patients at age of 60-85 years who had the MMSE-J score of 20-27 points and the Geriatric Depression Scale-Short Version-Japanese Version (GDS-S-J) score of 5 points or less. The patients were randomly allocated to either a treatment with 1 mg of scallop-derived Pls daily or a placebo treatment. The primary outcome was a 24 week change in the MMSE-J. The registered number of the trial is UMIN000014945.
Results: The MMSE-J total score improved statistically significantly in the Pls treatment but not in the placebo treatment, resulting in no significant between-treatment difference. With respect to one of the MMSE-J domains, orientation to place, the Pls treatment showed a significant improvement and the placebo treatment showed no such improvement; the between-treatment difference was statistically significant (p=0.003). The domain for orientation to time worsened significantly at endpoint in the placebo treatment, while the Pls treatment showed no worsening. However, the between-treatment difference failed to reach the statistical significance. No significant change was found in either treatment regarding the other MMSE-J domains.
Conclusion: These findings suggest that oral administration of 1 mg Pls enhances cognitive function of MCI patients, especially orientation to place.
Keywords: Mild cognitive impairment; Alzheimer’s disease; Plasmalogen; Mini mental state examination; Orientation to place
Introduction
The prevalence of Alzheimer’s disease (AD) has markedly increased worldwide. Early diagnosis and treatment of the preclinical stage of AD are, therefore, an urgent task for not only patients but for people living with dementia and social costs [1]. In general, mild cognitive impairment (MCI) is a clinical transition phase between normal elderly and AD. Internationally, the prevalence of MCI is estimated to be 15% to 20% in those at the age of 60 years and older [2]. It is also estimated that the progression from MCI to dementia occurs at annual rates of 8% to 15% [2]. Therefore, MCI is an important condition to identify and treat as early as possible. The interventions, especially pharmacological randomized control trials, have been attempted to delay MCI from the progress into AD. None of those, however, has been successful in delaying the progression from MCI to AD dementia [3-5]. Recently, it has become clear that plasmalogens (Pls), a special class of glycerophospholipids, are closely related to AD and MCI. Pls were decreased in the postmortem brain of AD patients [6-8] and Pls levels in the plasma and erythrocytes were lowered among AD and MCI patients [9,10].
Moreover, we have developed the simple method to extract Pls from animals [11] and subsequently have enabled to study preventive and therapeutic effects of Pls on animal AD model [12-15]. Interestingly, one of these experiments revealed that Pls resulted in a prominent improvement of space memory [16], which may be equivalent to human place-orientation. We have also reported that Pls may improve the cognitive function of mild AD patients in a randomized controlled trial (RCT) in which scallop-derived Pls were orally administered for 24 weeks [17]. In that study, a cognitive function was evaluated by the Mini Mental State Examination-Japanese (MMSE-J), but we did not examine the domain-specific changes of the MMSE-J. The present study examined the changes in the scores of individual domains of MMSE-J to assess the effects of scallop-derived plasmalogen on MCI patients in the previously reported RCT.
Methods
The study subjects in the present analysis were 178 patients with MCI out of the 276 patients with either MCI or AD who had completed the previously reported 24 week RCT [17]. Details of the methods have been described in the previous report [17]. In brief, the study was a multicenter, randomized, placebo-controlled trial of 276 patients at the age of 60 to 85 years who had a score of 20 to 27 points in the MMSE-J [18] and a score of 5 or less points in the Geriatric Depression Scale- Short Version-Japanese (GDS-S-J) [19]. The diagnosis of MCI was based on the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), and the MCI patients had 24 to 27 points of the MMSE-J [20]. The eligible patients were randomly allocated to either a treatment with 1 mg of Pls purified from scallop daily or a placebo treatment. The total score of MMSE-J was an outcome of the primary interest. All of the patients or their caretakers gave written informed consent. The trial was approved by the Institutional Review Boards of Fukuoka University Hospital (Fukuoka), Nihonbashi Sakura Clinic (Tokyo) and BOOCS Clinic Fukuoka (Fukuoka), was conducted in compliance with the Declaration of Helsinki.
The MMSE-J score was calculated on the basis of the response to 11-item questions at weeks 0, 12, 24 and 28. At each visit, the patient was accompanied by his/her caretaker. In the present analysis, the measurements at baseline and 24 weeks were used, and scores of the 11 domains were compared between the two treatments. Individual items of the MMSE-J are explained in Appendix 1.
The changes in the total score and domain-specific scores of the MMSE-J at endpoint were compared between the two using unpaired t-test. The after-treatment change from the baseline was statistically evaluated using paired t-test, and the mean change and 95% confidence interval (CI) were presented. Statistical analyses were carried out using Stata version 13 (StataCorp, College Station, TX). The registered number of the trial is UMIN000014945.
Results
The number of MCI patients in the Pls and placebo treatments was 90 and 88, respectively. No measurable difference was noted at baseline between the two treatments regarding sex, age, years of education, MMSE-J total score and domain-specific scores (Table 1).
Variable | Plasmalogen (n=90) | Placebo (n=88) | P value* |
---|---|---|---|
Male, n (%) | 37 (41.1) | 26 (29.5) | 0.12 |
Age in year | 75.8 (6.1) | 75.9 (5.5) | 0.90 |
Years of education† | 12.7 (2.9) | 12.1 (2.1) | 0.11 |
MMSE-J | 25.6 (1.3) | 25.6 (1.1) | 0.99 |
1. Orientation to time | 4.1 (1.2) | 4.1 (1.0) | 0.75 |
2. Orientation to place | 4.3 (0.6) | 4.4 (0.6) | 0.13 |
3. Three-word registration | 3.0 (0.2) | 3.0 (0.3) | 0.98 |
4. Attention and calculation | 4.2 (1.0) | 3.9 (1.2) | 0.07 |
5. Three-word recall | 1.4 (1.0) | 1.5 (1.1) | 0.55 |
6. Language (naming) | 2.0 (0.2) | 2.0 (0.2) | 0.99 |
7. Language (repeating) | 1.0 (0.1) | 1.0 (0.2) | 0.55 |
8. Language (3-step command) | 2.8 (0.5) | 2.8 (0.4) | 0.66 |
9. Language (reading) | 1.0 (0.0) | 1.0 (0.0) | ― |
10. Language (writing) | 1.0 (0.2) | 1.0 (0.2) | 0.98 |
11. Visual construction | 1.0 (0.2) | 1.0 (0.2) | 0.72 |
MMSE-J: Mini Mental State Examination-Japanese
Values are mean (SD) unless otherwise specified
* Chi-square test for proportion and unpaired t-test for mean
† Number of the patients was 86 in the plasmalogen treatment and 85 in the
placebo treatment
Table 1: Baseline characteristics.
The MMSE-J total score increased at 24 weeks by 0.59 (95% CI 0.13:1.05, p=0.01) in the Pls treatment and by 0.39 (95% CI -0.18:0.95, p=0.18) in the placebo treatment. However, the between-treatment difference in the change of the MMSE-J total score was not statistically significant (Figure 1).
Of the 11 domains of the MMSE-J, the orientation to place improved statistically significantly in the Pls treatment (p<0.0001), but not in the placebo treatment (p=0.66). The change in the domain score was significantly different between the two treatments (p=0.003) (Figure 1 and Table 2).
MMSE-J domain | Plasmalogen (n=90) | Placebo (n=88) | P-value | ||||
---|---|---|---|---|---|---|---|
Mean | SD | (95% CI) | Mean | SD | (95% CI) | ||
1. Orientation to time | -0.01 | 1.45 | (-0.31: 0.29) | -0.28 | 1.23 | (-0.54: -0.02) | 0.18 |
2. Orientation to place | 0.36 | 0.69 | (0.21: 0.50) | 0.03 | 0.73 | (-0.12: 0.19) | 0.003 |
3. Three-word registration | 0.02 | 0.26 | (-0.03: 0.08) | 0.05 | 0.26 | (-0.01: 0.10) | 0.55 |
4. Attention and calculation | 0.10 | 1.20 | (-0.15: 0.35) | 0.24 | 1.42 | (-0.06: 0.54) | 0.48 |
5. Three-word recall | 0.00 | 1.07 | (-0.22: 0.22) | 0.24 | 1.22 | (-0.02: 0.50) | 0.17 |
6. Language (naming) | 0.02 | 0.21 | (-0.02: 0.07) | 0.02 | 0.15 | (-0.01: 0.05) | 0.99 |
7. Language (repeating) | 0.01 | 0.11 | (-0.01: 0.03) | 0.02 | 0.15 | (-0.01: 0.05) | 0.55 |
8. Language (3-step command) | 0.06 | 0.57 | (-0.06: 0.17) | 0.07 | 0.52 | (-0.04: 0.18) | 0.88 |
9. Language (reading) | 0.00 | 0.00 | (―) | 0.00 | 0.00 | (―) | ― |
10. Language (writing) | 0.03 | 0.18 | (0.00: 0.07) | 0.02 | 0.21 | (-0.02: 0.07) | 0.72 |
11. Visual construction | 0.00 | 0.21 | (-0.04: 0.04) | -0.02 | 0.26 | (-0.08: 0.03) | 0.52 |
MMSE-J: Mini Mental State Examination-Japanese
Table 2: Mean difference from baseline by MMSE-J domains.
As regards the orientation to time, the Pls treatment showed no appreciable baseline-to-endpoint change (p=0.94) while the placebo treatment showed a statistically significant deterioration at endpoint compared to baseline (p=0.03). However, the between-treatment difference in the change of the score for the orientation to time was not statistically significant (Figure 1 and Table 2). Regarding the domains of calculation, registration and other domains, there was no significant change in either treatment. Nor was there a significant betweentreatment difference at endpoint (Table 2).
Further analyses were performed with stratification by age group and gender. The age was categorized into two classes at the median age in the original RCT of 276 patients, namely less than 77 years and 78 years or older. The differential improvement of the orientation-to-place score in the Pls treatment was observed in the patients aged 77 year or younger, but not in those aged 78 year or older (Table 3). Although the between-treatment difference was less marked, the favorable change of the orientation-to-place score in the Pls treatment was observed in both men and women (Table 4).
MMSE-J domain | Plasmalogen | Placebo | P-value | ||||
---|---|---|---|---|---|---|---|
Mean | SD | (95% CI) | Mean | SD | (95% CI) | ||
Aged ≤ 77 years | (n=48) | (n=52) | |||||
1. Orientation to time | -0.10 | 1.31 | (-0.48: 0.28) | -0.40 | 1.30 | (-0.77: -0.04) | 0.25 |
2. Orientation to place | 0.44 | 0.71 | (0.23: 0.64) | 0.00 | 0.71 | (-0.20: 0.20) | 0.003 |
3. Three-word registration | 0.02 | 0.25 | (-0.05: 0.09) | 0.04 | 0.28 | (-0.04: 0.12) | 0.74 |
4. Attention and calculation | 0.10 | 1.17 | (-0.24: 0.44) | 0.44 | 1.42 | (0.05: 0.84) | 0.20 |
5. Three-word recall | 0.25 | 1.06 | (-0.06: 0.56) | 0.31 | 1.13 | (-0.01: 0.62) | 0.79 |
6. Language (naming) | 0.04 | 0.29 | (-0.04: 0.13) | 0.04 | 0.19 | (-0.02: 0.09) | 0.95 |
7. Language (repeating) | 0.02 | 0.14 | (-0.02: 0.06) | 0.04 | 0.19 | (-0.02: 0.09) | 0.61 |
8. Language (3-step command) | 0.15 | 0.55 | (-0.01: 0.30) | 0.06 | 0.50 | (-0.08: 0.20) | 0.40 |
9. Language (reading) | 0.00 | 0.00 | (―) | 0.00 | 0.00 | (―) | - |
10. Language (writing) | 0.06 | 0.24 | (-0.01: 0.13) | 0.04 | 0.19 | (-0.02: 0.09) | 0.59 |
11. Visual construction | 0.02 | 0.25 | (-0.05: 0.09) | -0.02 | 0.31 | (-0.11: 0.07) | 0.48 |
Aged ≥ 78 years | (n=42) | (n=36) | |||||
1. Orientation to time | 0.10 | 1.61 | (-0.40: 0.60) | -0.11 | 1.12 | (-0.49: 0.27) | 0.52 |
2. Orientation to place | 0.26 | 0.66 | (0.05: 0.47) | 0.08 | 0.77 | (-0.18: 0.34) | 0.28 |
3. Three-word registration | 0.02 | 0.27 | (-0.06: 0.11) | 0.06 | 0.23 | (-0.02: 0.13) | 0.58 |
4. Attention and calculation | 0.10 | 1.25 | (-0.29: 0.48) | -0.06 | 1.39 | (-0.53: 0.42) | 0.62 |
5. Three-word recall | -0.29 | 1.02 | (-0.60: 0.03) | 0.14 | 1.36 | (-0.32: 0.60) | 0.12 |
6. Language (naming) | 0.00 | 0.00 | (―) | 0.00 | 0.00 | (―) | ― |
7. Language (repeating) | 0.00 | 0.00 | (―) | 0.00 | 0.00 | (―) | ― |
8. Language (3-step command) | -0.05 | 0.58 | (-0.23: 0.13) | 0.08 | 0.55 | (-0.10: 0.27) | 0.31 |
9. Language (reading) | 0.00 | 0.00 | (―) | 0.00 | 0.00 | (―) | ― |
10. Language (writing) | 0.00 | 0.00 | (―) | 0.00 | 0.24 | (-0.08: 0.08) | 1.00 |
11. Visual construction | -0.02 | 0.15 | (-0.07: 0.02) | -0.03 | 0.17 | (-0.08: 0.03) | 0.91 |
MMSE-J: Mini Mental State Examination-Japanese
Table 3: Mean difference from the baseline in the domains of MMSE-J by age group.
MMSE-J domain | Plasmalogen | Placebo | P-value | ||||
---|---|---|---|---|---|---|---|
Mean | SD | (95% CI) | Mean | SD | (95% CI) | ||
Males | (n=37) | (n=26) | |||||
1. Orientation to time | 0.24 | 1.62 | (-0.30: 0.78) | -0.50 | 1.61 | (-1.15: 0.15) | 0.08 |
2. Orientation to place | 0.30 | 0.66 | (0.08: 0.52) | -0.12 | 0.77 | (-0.42: 0.19) | 0.03 |
3. Three-word registration | -0.03 | 0.29 | (-0.12: 0.07) | 0.00 | 0.00 | (―) | 0.63 |
4. Attention and calculation | 0.16 | 1.42 | (-0.31: 0.64) | 0.38 | 1.60 | (-0.26: 1.03) | 0.56 |
5. Three-word recall | -0.16 | 0.99 | (-0.49: 0.17) | 0.12 | 1.21 | (-0.37: 0.60) | 0.32 |
6. Language (naming) | 0.05 | 0.33 | (-0.06: 0.16) | 0.00 | 0.00 | (―) | 0.41 |
7. Language (repeating) | 0.00 | 0.00 | (―) | 0.04 | 0.20 | (-0.04: 0.12) | 0.24 |
8. Language (3-step command) | 0.05 | 0.52 | (-0.12: 0.23) | -0.04 | 0.53 | (-0.25: 0.17) | 0.49 |
9. Language (reading) | 0.00 | 0.00 | (―) | 0.00 | 0.00 | (―) | ― |
10. Language (writing) | 0.05 | 0.23 | (-0.02: 0.13) | 0.08 | 0.27 | (-0.03: 0.19) | 0.72 |
11. Visual construction | -0.03 | 0.16 | (-0.08: 0.03) | -0.04 | 0.34 | (-0.18: 0.10) | 0.86 |
Females | (n=53) | (n=62) | |||||
1. Orientation to time | -0.19 | 1.30 | (-0.55: 0.17) | -0.19 | 1.04 | (-0.46: 0.07) | 0.98 |
2. Orientation to place | 0.40 | 0.72 | (0.20: 0.59) | 0.10 | 0.72 | (-0.09: 0.28) | 0.03 |
3. Three-word registration | 0.06 | 0.23 | (-0.01: 0.12) | 0.06 | 0.31 | (-0.01: 0.14) | 0.88 |
4. Attention and calculation | 0.06 | 1.03 | (-0.23: 0.34) | 0.18 | 1.35 | (-0.17: 0.52) | 0.60 |
5. Three-word recall | 0.11 | 1.12 | (-0.20: 0.42) | 0.29 | 1.23 | (-0.02: 0.60) | 0.43 |
6. Language (naming) | 0.00 | 0.00 | (―) | 0.03 | 0.18 | (-0.01: 0.08) | 0.19 |
7. Language (repeating) | 0.02 | 0.14 | (-0.02: 0.06) | 0.02 | 0.13 | (-0.02: 0.05) | 0.91 |
8. Language (3-step command) | 0.06 | 0.60 | (-0.11: 0.22) | 0.11 | 0.52 | (-0.02: 0.24) | 0.59 |
9. Language (reading) | 0.00 | 0.00 | (―) | 0.00 | 0.00 | (―) | ― |
10. Language (writing) | 0.02 | 0.14 | (-0.02: 0.06) | 0.00 | 0.18 | (-0.05: 0.05) | 0.54 |
11. Visual construction | 0.02 | 0.24 | (-0.05: 0.08) | -0.02 | 0.22 | (-0.07: 0.04) | 0.42 |
MMSE-J: Mini Mental State Examination-Japanese
Table 4: Mean difference from the baseline in the domains of MMSE-J by gender.
The domain-specific analysis was repeated in the patients with mild AD (n=98). There was no measurable within-treatment change in either treatment and no material between-treatment difference in the change regarding any of the 11 domains of MMSE-J (Appendix 2).
Discussion
Our previous paper suggested that ingestion of Pls was effective in improving the cognitive function as captured by WMS-R among patients with mild AD [17]. Its effectiveness against MCI was, however, not observed; WMS-R improved in both Pls and placebo treatments, resulting in no significant between-treatment difference.
The present study examined the change in MMSE-J before and after Pls administration, focusing on MCI patients out of the patients enrolled in the previous RCT [17]. While the MMSE-J total score improved statistically significantly in the Pls treatment, the change was not significantly different from that observed in the placebo treatment. However, the analysis on individual domains of the MMSE-J revealed that the orientation to place improved significantly and differentially in the Pls treatment alone. The lack of such an improvement among the patients 78 year or older suggests that the effects of Pls on MCI may be age-dependent. Lack of an improvement in the orientation to time by Pls is contrasting to the finding on place-orientation. The finding is, however, not necessarily peculiar in view of the temporal occurrence of disorientation to time and place. Orientation to time is usually disturbed at first, and then orientation to place is lost in the progression form MCI to AD [21,22]. Thus it is not a far-fetched explanation that recovery of the late-disturbed orientation to place precedes that of orientation to time. Importantly, the finding on the orientation to time suggests that Pls may prevent deterioration in orientation to time. Elsewhere, it has been demonstrated that Pls improve the spatial memory using the Morris Water Maze task [16], which is analogous to the place-orientation of the MMSE-J cognitive domains. Pls supplementation restored hippocampal levels of Pls and enhanced memory-related molecular signaling in model mice [16]. Therefore, these results strongly indicate that Pls improve the spatial memory in MCI patients as with animal AD models. Moreover, these findings are thought to have clinical importance since previous studies reported that the orientation to place of MMSE was an important predictor for elderly fall [23].
As discussed in our previous paper, ingestion of as small an amount of Pls as 1.0 mg per day has efficacy probably owing to its hormonelike action [24-26]. Pls are normally produced in peroxisomes and the ER in cells. However, its production capacity declines along with the occurrence and worsening of neuroinflammation, whereas Pls consumption increases. As a result, the total amount of Pls is decreased, which is thought to lead to the increase of ɤ-secretase [27] and accumulation of amyloid-β. It has become known that Pls are abundant in lipid rafts of cell membrane and improve cognitive function via the complicated process in cells [28].
Limitation
A limitation in this study is that the administration period of 24 weeks may be too short to fully evaluate MCI patients. Another weakness is that the cognitive function was assessed by the MMSE-J, which may be influenced by learning effect. However, such an effect was not observed in the placebo treatment regarding the orientation to place. Thus the present findings cannot be explained by learning effect alone. It should be also noted that the present finding on the orientation to place may have been due to chance. A statistically significant difference may occur by chance in the multiple comparisons. However, the between-treatment difference in the orientation to place was statistically significant (p=0.03) even after Bonferroni adjustment was made for the multiple comparisons. Further research is needed to conduct a follow-up study on change in MMSE-J along with measurement of blood Pls and MRI.
Conclusion
The present analysis assessed the 24 week change in the domainspecific scores of the MMSE-J among 178 patients with MCI enrolled in the previously reported trial. With respect to the orientation to place, the Pls treatment showed a significant improvement and the placebo treatment showed no such improvement. The between-treatment difference was highly significant (p=0.003). Oral administration of 1 mg Pls enhances cognitive function of MCI patients, especially the orientation to place.
Conflicts of Interest
TF and SM have applied for patents on method for manufacturing ether phospholipid (patent application number: PCT/JP2015/63617, PCT/JP2015/63740). TY, TA, MI, YT, and CW declare that they have no conflicts of interest.
Acknowledgement
The authors are grateful to all patients and caretakers who participated in the study. The following study physicians contributed to implementation of the trial: E Nishikawa (Nishikawa-naika Clinic, Shimonoseki), H Fujino (Fujino Clinic, Yanagawa), H Matsuo (Matsuo Hospital, Fukuoka), H Nawata (Muta Hospital, Fukuoka), K Fukuyama (Hasami Hospital, Higashisonogi), K Irie (Hakujyuji Hospital, Fukuoka), K Saito, N Shinfuku (BOOCS Clinic Fukuoka, Fukuoka), K Serikawa (Monowasure Mental Clinic, Fukuoka), K Takasaki (Takasaki Neurosurgery Clinic, Kasuya), M Ichimaru (BOOCS Holistic Clinic Tokyo, Tokyo), M Kinoshita (Nagata Hospital, Yanagawa), M Munaka (Hayama Clinic, Munakata), N Araki (Utsunomiya Rehabilitation Hospital, Utsunomiya), S Nakamura (Sangenjaya Nakamura Mental Clinic, Tokyo), S Ouma (Fukuoka University Hospital, Fukuoka), S Nakano (Nihonbashi Sakura Clinic, Tokyo), T Asada (Olive Clinic Ochanomizu, Tokyo, Memory Clinic Ochanomizu, Tokyo), T Kaneko (Kaneko Hospital, Yanagawa), T Kinoshita (Nozomi Memory Clinic, Mitaka), T Yamada (Nishino Hospital, Kitakyushu, Tokorozawa Meisei Hospital, Tokorozawa), T Yosimatsu (Mito Hospital, Kasuya), Y Nakayama (Nakayoshi-Clinic, Kasuya), Y Sekine (Sekine Clinic, Hirakata). The authors are grateful to Dr. Suminori Kono, MedStat Corporation, Fukuoka, Japan for his support in data analysis and preparation of the manuscript. The study was funded by the Japanese Plasmalogen Society (Pls2014-01), Fukuoka, Japan.
References
- World Alzheimer’s Report (2016) Improving healthcare for people living with dementia: Coverage, quality and costs now and in the future. Alzheimer's disease International, London.
- Petersen RC (2016) Mild cognitive impairment. Continuum (Minneap Minn) 22: 404-418.
- Doody RS, Ferris SH, Salloway S, Sun Y, Goldman R, et al. (2009) Donepezil treatment of patients with MCI: A 48 week randomized, placebo-controlled trial. Neurology 72: 1555-1561.
- Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, et al. (2007) Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment: The InDDEx study. Lancet Neurol 6: 501-512.
- Winblad B, Gauthier S, Scinto L, Feldman H, Wilcock GK, et al. (2008) Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 70: 2024-2035.
- Ginsberg L, Rafique S, Xuereb JH, Rapoport SI, Gershfeld NL (1995) Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer's disease brain. Brain Res 698: 223-226.
- Guan Z, Wang Y, Cairns NJ, Lantos PL, Dallner G, et al. (1999) Decrease and structural modifications of phosphatidylethanolamine plasmalogen in the brain with Alzheimer’s disease. J Neuropathol Exp Neurol 58: 740-747.
- Han X, Holtzman DM, McKeel DW (2001) Plasmalogen deficiency in early Alzheimer's disease subjects and in animal models: Molecular characterization using electrospray ionization mass spectrometry. J Neurochem 77: 1168-1180.
- Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, et al. (2007) Peripheral ethanolamine plasmalogen deficiency: A logical causative factor in Alzheimer’s disease and dementia. J Lipid Res 48: 2485-2498.
- Oma S, Mawatari S, Saito K, Wakana C, Tsuboi Y, et al. (2012) Changes in phospholipid composition of erythrocyte membrane in Alzheimer’s disease. Dement Geriatr Cogn Disord Extra 2: 298-303.
- Mawatari S, Okuma Y, Fujino T (2007) Separation of intact plasmalogens and all other phospholipids by a single run of high-performance liquid chromatography. Anal Biochem 370: 54-59.
- Mawatari S, Katafuchi T, Miake K, Fujino T (2012) Dietary plasmalogen increases erythrocyte membrane plasmalogen in rats. Lipids Health Dis 11: 161.
- Katafuchi T, Ifuku M, Mawatari S, Noda M, Miake K, et al. (2012) Effects of plasmalogens on systemic lipopolysaccharide-induced glial activation and ß-amyloid accumulation in adult mice. Ann N Y Acad Sci 1262: 85-92.
- Hossain MS, Ifuku M, Take S, Kawamura J, Miake K, et al. (2013) Plasmalogens rescue neuronal cell death through an activation of AKT and ERK survival signaling. PLoS One 8: e83508.
- Hossain MS, Abe Y, Ali F, Youssef M, Honsho M, et al. (2017) Reduction of ether-type glycerophospholipids, plasmalogens, by NF-κB signal leading to microglial activation. J Neurosci 37: 4074-4092.
- Hossain MS, Ifuku M, Abe Y, Honsho M, Kotoura S, et al. (2017) Involvement of vinyl ether-linked glycerophospholipids, plasmalogens, in memory function by accelerating brain-derived neurotrophic factor-TrkB signaling in the mouse hippocampus. PLoS Biol (under revision).
- Fujino T, Yamada T, Asada T, Tsuboi Y, Wakana C, et al. (2017) Efficacy and blood plasmalogen changes by oral administration of plasmalogen in patients with mild Alzheimer's disease and mild cognitive impairment: A multicenter, randomized, double-blind, placebo-controlled trial. EBioMedicine 17: 199-205.
- Sugishita M, Hemmi I, Jadni (2010) Validity and reliability of the min mental state examination-japanese (MMSE-J): A preliminary report. Jap J Cogn Neurosci 12: 186-190.
- Sugishita M, Asada T (2009) Preparation of geriatric depression scale-short version–Japanese, GDS-S-J. Jap J Cogn Neurosci 11: 87-90.
- Solfrizzi V, Panza F, Colacicco AM, D'Introno A, Capurso C, et al. (2004) Longitudinal study on aging working group vascular risk factors, incidence of MCI and rates of progression to dementia. Neurology 63: 1882-1891.
- Inamura K, Shinagawa S (2013) Core symptom: Cognitive impairment. Nakashima K edited, Handbook on Dementia 28-35, Igaku-Shoin Ltd. Tokyo.
- Hosák L, Hrdlicka M (2017) Psychiatry and pedopsychiatry 57, Charles University in Prague, Karolinum Press.
- Ramirez D, Wood RC, Becho J, Owings K, Markides K, et al. (2010) Mini-mental state exam domains predict falls in an elderly population: Follow-up from the Hispanic established populations for epidemiologic studies of the elderly (H-EPESE) study. Ethn Dis 20: 48-52.
- Hossain MS, Mineno K, Katafuchi T (2016) Neuronal orphan g-protein coupled receptor proteins mediate plasmalogens-induced activation of ERK and Akt signaling. PLoS One 11: e0150846.
- New DC, Wong YH (2007) Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progression. J Mol Signal 2: 2.
- Chini B, Parenti M (2004) G-protein coupled receptors in lipid rats and caveolae; How, when and why do they go there? J Mol Endocrinol 32: 325-338.
- Onodera T, Futai E, Kan E, Abe N, Uchida T, et al. (2015) Phosphatidyl ethanolamine plasmalogen enhances the inhibiting effect of phosphatidyl ethanolamine on γ-secretase activity. J Biochem 157: 301-309.
- Pike LJ, Han X, Chung KN, Gross RW (2002) Lipid rafts are enriched in arachidonic acid and plasmenyl ethanolamine and their composition is independent of caveolin-1 expression: A quantitative electrospray ionization/mass spectrometric analysis. Biochemistry 41: 2075-2088.
Citation: Fujino T, Yamada T, Asada T, Ichimaru M, Tsuboi Y, et al. (2018) Effects of Plasmalogen on Patients with Mild Cognitive Impairment: A Randomized, Placebo- Controlled Trial in Japan. J Alzheimers Dis Parkinsonism 8: 419. DOI: 10.4172/2161-0460.1000419
Copyright: ©2018 Fujino T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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