Investigating the Efficacy of Ergothioneine to Delay Cognitive Decline

Investigating the Efficacy of Ergothioneine to Delay Cognitive Decline in Mild Cognitively Impaired Subjects

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.

Investigational compound and placebo coded by manufacturer. Codes provided in envelope will only be unsealed at the end of the study (data assessment) or in case of emergency.

Subjects will consume 25mg ergothioneine (capsule), 3 times weekly (Monday, Wednesday, and Friday) for a total of 52 weeks.

Subjects will be given placebo (99% microcrystalline cellulose, 1% magnesium stearate; capsule), 3 times weekly (Monday, Wednesday, and Friday) for a total of 52 weeks.

Ergothioneine is naturally occurring thiol compound obtained solely from diet in humans. Ergothioneine is widely reported to be a natural antioxidant and anti-inflammatory compound. In addition we hypothesize that this compound will be beneficial in improving cognition.

30 point questionnaire to test for cognitive function (scoring of cognitive impairment). For the intervention group no change or an increase in test score is expected compared with placebo control. The aggregated scores from the battery of cognitive function assessments (primary outcomes 1 to 8) will be assessed by a panel of psychological consultants to give an overall assessment of cognitive function.

Numerical scale used to characterize the severity of dementia. Assesses the six domains of cognitive and functional performance applicable to dementia; Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. For clinical dementia rating a decrease in CDR scale is expected.

The Rey Auditory Verbal Learning Test (RAVLT) evaluates short-term auditory-verbal memory, rate of learning, learning strategies, retroactive, and proactive interference, presence of confabulation of confusion in memory processes, retention of information, and differences between learning and retrieval. Participants are given a list of 15 unrelated words repeated over five different trials and are asked to repeat. Another list of 15 unrelated words are given and the client must again repeat the original list of 15 words and then again after 30 minutes.

The digit span task is a measure of working memory, based on a person's ability to recall a sequence of numerical digits. An increase or no change in score is expected for the intervention group.

The block design test examines the spatial visualization ability and motor skills of an individual. A decrease in time taken to complete the assessment is expected.

The symbol digit modality is a test for assessing cognitive impairment through speed and visual processing abilities of an individual. An increase in test scores are expected for the intervention group.

The Boston Naming Test presents individuals with a range of drawing of common objects and are asked to name them one at a time. This tests for dementia and cognitive decline. An increase in test scores and lower error rate is expected within the intervention group.

The colour trails test assesses sustained and dividend attention. A decrease in time taken to complete the assessment is expected.

Changes in brain structure including grey and white matter will be assessed using magnetic resonance imaging. A reduction or absence of change in grey and white matter atrophy is expected in the intervention group.

Magnetic resonance imaging will be used to determine hippocampal volume. A reduction or absence of change in hippocampal atrophy is expected in the intervention group.

A range of blood (allantoin, protein carbonylation, hercynine) and urinary biomarkers (F2-isoprostanes, 8OHdG, 8OHG) of oxidative damage will be measured at various timepoints throughout the study, utilizing liquid chromatography mass spectrometry. A reduction in these blood and urinary oxidative damage products is expected in the intervention group.

Over the course of the study a reduction in inflammatory cytokines (C-reactive protein, tumor necrosis factor alpha, interleukin-1 etc.) is expected in the intervention group, as determined through enzyme-linked immunosorbent assay

The geriatric depression scale is a self-reported assessment to identify depression in elderly individuals, through a series of questions. Scores are based on the sum of the answers indicating depressive symptoms are tallied and give an indication of the likelihood of depression. At the conclusion of the study a reduction or absence of change is expected in the geriatric depression scale.

The geriatric anxiety inventory is a self-reported assessment to identify anxiety syndromes in elderly individuals, through a series of questions. At the conclusion of the study a reduction or absence of change is expected in the geriatric anxiety score.

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

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