Research

Research

Prediction of the number of people with dementia

According to World Alzheimer Report 2015 from Alzheimer’s Disease International, 46.8 million people worldwide are living with dementia in 2015.

This number will almost double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050. It is well known there is still no drug capable of improving Alzheimer’s disease.

Previous Study (1)

Ginsberg has first reported the close correlation between plasmalogen and Alzheimer’s disease, that is, plasmalogen was decreased in post mortem brain samples of Alzheimer’s disease, compared with in other neurodegenerative diseases.

Previous Study (2)

Goodenowe showed that circulating plasmalogen was decreased in serum from patients with Alzheimer’s disease and the decrease of the plasmalogen correlated with the severity of dementia.

Background

First, let us begin with the background of our study. These our studies made it possible for us to perform our clinical study.

This slide outlines the progress of research on Pls, focusing on their association with Alzheimer’s disease. Research on Alzheimer’s disease was initially led by the United States; in 1995 and 1999, reduced levels of Pls in the brains of cadavers with Alzheimer’s disease were noted, and, subsequently, in 2007, reductions in the serum levels of Pls in living patients with Alzheimer’s disease were reported.

In Japan, we succeeded in developing a new, advanced detection method for Pls in 2007. We also developed a method for the extraction and production of high-purity Pls in 2009. The development of these methods facilitated the administration of Pls to animals and humans. Furthermore, we published research papers in 2012 and 2013 reporting that Pls were effective in rats with Alzheimer’s disease, and in 2012 that the levels of Pls were reduced in the erythrocytes of patients with the disease. We conducted a randomized double-blind placebo-controlled trial involving humans from Nov. 2014 to Apr. 2016

Extraction Method of Plasmalogen

It is described that high-performance liquid chromatography can separate intact
ethanolamine plasmalogens and choline plasmalogens as well as all other phospholipid classes by a single chromatographic run.

This slide shows the results of animal experiments using the plasmalogen which we extracted. Left panel shows the formations of dendrites in no application of plasmalogen. Right panel shows the those in application of plasmalogen, DIV6 means the sixth day from embryo, DIV 14 the fourteenth day embryo. These data shows direct application of plasmalogen enhances the formation of dendrites in primary hippocampal cultured neurons.

This figure explains plasmalogen enhance the neurogenesis the memory-related hippocampal cells of mice immunostaining data. As shown in the right panel, the
Plasmalogen-diet mice showed more positive neurons in the dentate gyrus, compared with normal diet.

Mechanisms of Plasmogen Effect (3)

It is already known that Lipopolysaccharide (LPS), one of inflammatory agent, promotes amyloid-β accumulations, which induce Alzheimer’s disease. As shown at the LPS column, the cell is stained green, indicating that amyloidosis took place in the CA1 area of the hippocampus, after LPS administration. In contrast, after the simultaneous administration of LPS and Plasmalogen, as shown in the LPS + Plasmalogen column, the cell was not stained green. This indicates that amyloidosis did not occur when Plasmalogen were administered.

Effects of Plasmalogen in AD model Animal

Plasmalogen promotes neurogenesis in senescence-accelerated mice and normal mice. This results in effective treatment of Alzheimer’s Disease. Plasmalogen inhibits neuroinflammation and amyloid β-protein accumulation in the brain. This results in effective prevention of Alzheimer’s Disease.

Mechanisms of Pls Effect (4)

Knock down of plasmalogen synthesizing enzyme (GNPAT) by sh-RNA in the hippocampus reduced plasmalogen and impairs spatial memory. Dietary plasmalogen for 6 weeks increased hippocampal plasmalogen and enhanced memory task performance. Dietary plasmalogen activated Akt and ERK1/2, in the hippocampus, to phosphorylate CREB, then induced expression of brain-derived neurotrophic factor (BDNF), which is well known to enhance memory function by affecting neuronal plasticity and synapse/spine formation. plasmalogen are rich in membrane lipid rafts and dietary plasmalogen result in a localization of BDNF receptor, TrkB in the lipid raft. These findings suggest that plasmalogen may enhance the memory by activating BDNF- TrkB signaling in the hippocampus.

Clinical Study (RCT) of Plasmalogen (1)

Here, I’ll talk about our Randomized Controlled Trial to examine the effects of Plasmalogen on patients with mild Alzheimer’s disease and Mild Cognitive Impairment.

Study Design

Here is our study design. 328 patients, aged 60-85 years. They were randomized to receive either 1mg/day plasmalogens or placebo for 24 weeks. We assessed the safety to these patients by monthly clinic visit. Of 328 patients enrolled, 276 patients completed the 24- week follow-up.

Study Participants

Here is a breakdown of the study participants. Number of cases was 178 in Mild Cognitive Impairment, 98 in mild Alzheimer’s Disease.

Improvement of cognitive function in mild AD

The sub-analysis by sex and age in patients with mild Alzheimer’s Disease. Closed circle indicates Plasmalogen group, and open circle does placebo group, respectively. In female subjects, WMS-R, the marker of memory function, improved significantly in Plasmalogen group and there were significant differences between Plasmalogen and placebo groups as shown in the left panel. Right panel indicates the difference by age. In 77 or younger group, WMS-R significantly improved in Plasmalogen group and showed the significant differences between Plasmalogen and placebo groups.

Changes of Blood Plasmalogen

Here we did the sub-analysis by sex and age in patients with mild Alzheimer’s Disease. Closed circle indicates Plasmalogen group, and open circle does placebo group, respectively. In female subjects, WMS-R, the marker of memory function, improved significantly in Plasmalogen group and there were significant differences between Plasmalogen and placebo groups as shown in the left panel. Right panel indicates the difference by age. In 77 or younger group, WMS-R significantly improved in Plasmalogen group and showed the significant differences between Plasmalogen and placebo groups.

This slide shows the changes in plasma and erythrocyte Plasmalogen levels following oral administration of Plasmalogen. Closed circle indicates Plasmalogen group. Open circle shows placebo group. In the placebo group, Plasmalogen level in plasma significantly decreased at endpoint, and the significant difference between Plasmalogen and placebo groups was observed.

Improve of cognitive function in MCI

Of the 11 domains of the MMSE-J, the orientation to place improved statistically significantly in the Plasmalogen group (p<0.0001), but not in the placebo group (p=0.66). The change in the domain score was significantly different between the two groups (p=0.003).

Clinical Study (Open-Label) of plasmalogen{2}

As for moderate and severe Alzheimer’s disease, we conducted an open-label trial.

Study Participants

Here is a breakdown of the study participants. The number of cases was 57 in moderate Alzheimer’s disease and 18 in severe Alzheimer’s disease.

Study Design

Here is our study design for an open-label trial. Participants received 1mg Pls orally per day for 3 months.

Improvement of cognitive function in moderate to severe AD

As shown in the left panel, 52.6 % of moderate AD improved significantly, while35.1% of those unchanged and 12.3% of those worsened. In severe AD, as shown in the right panel, 27.8% of those improved significantly. While 27.8% of those unchanged and 16.7% worsened.

Lastly, I will talk about discussion and conclusions. To our knowledge, this study is the first trial in the world that efficacy and change of blood plasmalogens by oral administration of plasmalogen were examined in patients with Alzheimer’s disease and mild cognitive impairment.

These results suggest that:

1) Oral administration of plasmalogen extracted from scallop improves cognitive functions in Alzheimer’s disease

2) Blood plasmalogen is useful for the assessment of cognitive functions, including the differentiation between Mild Cognitive Impairment and mild Alzheimer’s disease.

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