Investigating the Efficacy of Ergothioneine to Delay Cognitive Decline

With the growing burden of dementia (including Alzheimer's disease), and the lack of efficacious therapies, there is an urgent need to identify new therapeutics.

Ergothioneine (ET) is a naturally occurring thiol derivative of histidine, obtained solely through diet and is able to accumulate in the body and brain, through the action of a specific transporter, OCTN1. In addition to a wide variety of in vitro and in vivo (animal) studies demonstrating the antioxidant, anti-inflammatory properties of ET, several studies have demonstrated the neuroprotective potential of ET in various cell and animal models.

Based on the ability of ET to counteract the underlying pathology of AD dementia, it is hypothesize that ET supplementation may prevent cognitive decline, especially in individuals at risk of cognitive impairment. This will be assessed using a randomized, double blinded, placebo-controlled, intervention study to test the ability of ET to delay or reverse cognitive impairment in elderly individuals with mild cognitive impairment.

Ergothioneine (ET) is a naturally occurring thiol/thione obtained in humans solely through diet. It is able to accumulate in specific cells and tissues (including the brain), via a specific transporter, OCTN1, at high levels. Although the exact physiological function(s) of ET have yet to be elucidated, numerous reports have demonstrated that this compound can scavenge reactive oxygen species (such as hydroxyl radicals, hypochlorous acid, and peroxynitrite), modulate inflammation, and chelate divalent metal ions. These processes are all implicated in the pathology of dementia. Various studies in cell and animal models have also highlighted the potential neuroprotective capabilities of ET following insult by various neurotoxic agents such as cisplatin and amyloid beta peptide.

Studies demonstrated that ET dose-dependently protected PC12 cells against beta amyloid-induced apoptotic death, and later was shown to protect against neuronal injury caused by direct administration of amyloid beta into the mouse hippocampus, thereby increasing scores in active avoidance and water maze tests. ET also dose-dependently extend lifespan of a transgenic Caenorhabditis elegans model of AD by reducing amyloid oligomer formation. Other studies also demonstrated that ET is also able to attenuate oxidative stress and prevents cognitive deficits in a D-galactose-induced dementia mouse model; protect against N-methyl-D-aspartate-induced cytotoxicity in rat retinal neurons; and prevent cisplatin-induced neuronal damage in cell cultures and mice.

To date no studies have evaluated the therapeutic ability of ET, clinically, to delay or halt cognitive decline. Prior studies administering pure ET to humans provide insights into the pharmacokinetics and demonstrate the safety of this compound, laying the foundations for this clinical study. The present proposal will shed light onto a relatively lesser known natural compound and the therapeutic capabilities it possesses, which has the potential to significantly impact the economic and societal burdens of dementia.

Eligibility Criteria:
Inclusion Criteria:

* Elderly individuals 60 - 90 years of age
* Chinese ethnicity (from other local cohort studies)
* Demonstrate amnestic mild cognitive impairment (assessed by panel of psychiatrists)
* Independent and able to travel to study site without assistance
* No other severe underlying conditions or terminal illnesses
* Capable of understanding the study and requirements and able to provide informed consent to participate
* Willing to commit to the year-long study, comply with study administration and periodic blood and urine sampling

Exclusion Criteria:

* Inability to understand the risks and requirements of the study for any reason
* Any intolerance to lactose, and/or allergies to mushrooms
* History of cardiovascular complications, diabetes, hypertension or hypercholesterolemia, or other pre-existing condition that may prevent them from completing the study
* Evidence of anaemia or other significant haematological conditions
* History or mental illness, depression or other underlying psychiatric illnesses
* History of drug or alcohol abuse
* Involvement in another study requiring administration of an investigational compound in the past 30 days
* Subjects whose blood analysis reveal and extremes of liver or kidney function markers (from baseline screening)
* Deemed unfit for any reason as determined by the principal/co-investigator