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

Abstract

BackgroundPlasmalogens (Pls) reportedly decreased in postmortem brain and in the blood of patients with Alzheimer's disease (AD). Recently we showed that intraperitoneal administration of Pls improved cognitive function in experimental animals. In the present trial, we tested the efficacy of oral administration of scallop-derived purified Pls with respect to cognitive function and blood Pls changes in patients with mild AD and mild cognitive impairment (MCI).MethodsThe study was a multicenter, randomized, double-blind, placebo-controlled trial of 24 weeks. Participants were 328 patients aged 60 to 85 years who had 20 to 27 points in Mini Mental State Examination-Japanese (MMSE-J) score and five or less points in Geriatric Depression Scale-Short Version-Japanese (GDS-S-J). They were randomized to receive either 1 mg/day of Pls purified from scallop or placebo. The patients and study physicians were masked to the assignment. The primary outcome was MMSE-J. The secondary outcomes included Wechsler Memory Scale-Revised (WMS-R), GDS-S-J and concentration of phosphatidyl ethanolamine plasmalogens (PlsPE) in erythrocyte membrane and plasma. This trial is registered with the University Hospital Medical Information Network, number UMIN000014945.FindingsOf 328 patients enrolled, 276 patients completed the trial (140 in the treatment group and 136 in the placebo group). In an intention-to-treat analysis including both mild AD (20 ≤ MMSE-J ≤ 23) and MCI (24 ≤ MMSE-J ≤ 27), no significant difference was shown between the treatment and placebo groups in the primary and secondary outcomes, with no severe adverse events in either group. In mild AD patients, WMS-R improved significantly in the treatment group, and the between group difference was nearly significant (P = 0.067). In a subgroup analysis of mild AD patients, WMS-R significantly improved among females and those aged below 77 years in the treatment group, and the between-group differences were statistically significant in females (P = 0.017) and in those aged below 77 years (P = 0.029). Patients with mild AD showed a significantly greater decrease in plasma PlsPE in the placebo group than in the treatment group.InterpretationOral administration of scallop-derived purified Pls may improve cognitive functions of mild AD.Funding.

Improvement of Blood Plasmalogens and Clinical Symptoms in Parkinson’s Disease by Oral Administration of Ether Phospholipids: A Preliminary Report

“…Furthermore, some clinical symptoms of PD were improved concomitantly. Beneficial effects of the same ether phospholipids ingestion were also observed in patients with AD [15]. e oral ingestion of purified ether phospholipids derived from scallop improved some cognitive functions of AD [15].…”

“…It is reported that plasmalogens are abundant in the brain, retina, leukocytes (immune cells), sperm, heart, and skeletal muscle in mammals [10,11]. Vinyl ether bond at the sn-1 position makes plasmalogens more susceptible to oxidative stress than corresponding ester-bonded glycerophospholipids [11][12][13][14][15]. erefore, plasmalogens may act as antioxidation and protect cells from oxidative stress [13,14].…”

“…We previously reported efficacy of oral administration of purified ether phospholipids derived from scallop to cognitive functions in patients with mild Alzheimer's disease (AD) and mild cognitive impairment (MCI) by a multicenter, randomized, double-blind, placebo-controlled trial [15,16]. In that study, 140 patients with AD received 1 mg/day of ether phospholipids derived from scallop for 24 weeks, and no serious adverse events have been observed [15].…”

Plasmalogen deficiency and neuropathology in Alzheimer's disease: Causation or coincidence?

“…Comparatively, lower dose of plasmalogens (1 mg twice daily) and the labile nature of the vinyl‐ether bond might have limited the absorption of the intact molecule and might have contributed to the lack of response in terms of plasmalogen levels in the blood as well as the cognitive function (Mini Mental State Exam‐Japanese version or Welchsler Memory Scale‐Revised), except for female patients with mild AD given plasmalogen supplementation who showed a significant improvement in Welchsler Memory Scale‐Revised compared with the placebo group. The authors suggested that studies with longer duration and observation of converters from MCI to AD might be needed to evaluate the efficacy of plasmalogen supplementation because the study duration of the study might be too short [62]. The dose of plasmalogens used in this study (2 mg/day, which amounts to about 0.03 mg/kg) is an inadequate dosage in our view for elevating tissue levels.…”

Breast Milk Lipidomics: Insights to Infant Health Requirements and Targeted Strategies for the Vulnerable

“…6 Of note, lower levels of plasmalogens have been reported in patients with Alzheimer's disease but not in patients with other neurodegenerative disorders, suggesting plasmalogen deficiency may be a specific biomarker for Alzheimer's disease. 7,8 Lipids in breast milk are contained within milk fat globules, which consist of a trilayer membrane of polar lipids, cholesterol, enzymes, and glycoproteins surrounding a triglyceride core. 9 A study in rats demonstrated that formula supplemented with bovine milk fat globule membrane (MFGM) normalized intestinal development compared with control formula, with intestinal readouts similar to rats receiving mothers' milk.…”