Investigating the Efficacy of Ergothioneine to Delay Cognitive Decline (Pilot)

Phase 1

Completed

• Conditions: Mild Cognitive Impairment
• Interventions: Drug: Placebo; Drug: L-ergothioneine

• Registration Number: NCT03641404
• Lead Sponsor: National University Hospital, Singapore

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Status Verified: 2018-05
• Study First Submitted: 2018-07-16
• Study First Submitted QC: 2018-08-19
• Study First Posted: 2018-08-22
• Study Start: 2019-08-01
• Primary Completion: 2023-12-31
• Study Completion: 2023-12-31
• Last Update Submitted: 2025-06-05
• Last Update Posted: 2025-06-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Demonstrate safety of oral ergothioneine supplementation	12 months	This study will evaluate the safety oral ergothioneine supplementation over a period of 12 months. Safety is monitored through monthly visits (assessment and feedback on adverse reactions) and quarterly blood assessment (blood counts, liver and renal function).
Demonstrating uptake of ergothioneine following dietary supplementation	12 months	This pilot study will evaluate the ability of oral ergothioneine supplementation to raise levels of ergothioneine in the body (blood measurements) over the one year period
Evaluating the impact of ergothioneine supplementation to modulate oxidative damage	Over 12 months	The ability of oral ergothioneine supplementation to modulate oxidative stress in the subjects will be assessed through changes in plasma and urinary oxidative damage biomarkers collected at baseline and quarterly (every 3 months) over the 12-month study duration.
Evaluate the impact of ergothioneine supplementation to modulate inflammation	Over 12 months	The ability of oral ergothioneine supplementation to modulate inflammatory status in the subjects will be assessed through measurement of inflammatory cytokines in the plasma at baseline and quarterly (every 3 months) over the 12-month study duration.

Secondary Outcome Measures

Name	Time	Method
Neuropsychological assessment battery: Colour Trials Test (Cognitive function assessments)	12 months (assessed baseline, 6 months and 12 months)	The colour trails test assesses sustained and dividend attention, and executive function involving parts 1 - connecting numbered circles in sequence and part 2 - requires alternating between circles of different colours (pink and yellow) while connecting them in numerical order. The time taken to complete parts 1 and 2 are recorded (as well as errors) with faster time indicating better attention and cognitive flexibility.
Neuropsychological assessment battery: Semantic Verbal Fluency Test (Cognitive function assessment)	12 months (assessed baseline, 6 months and 12 months)	The Semantic Verbal Task involves asking the subject to name as many animals (part 1) and fruits (part 2) as they can in 60 seconds, which each correct answer adding one point. Scores are tallied from parts 1 and 2, with higher scores (no limit, only based on time) indicating better language, semantic memory, and processing ability.
Evaluation of Geriatric Anxiety Inventory (Neuropsycological assessment)	12 months (assessed baseline, 6 months and 12 months)	The geriatric anxiety inventory is a self-reported assessment to identify anxiety syndromes in elderly individuals, through a series of 20 questions (with minimum of 0 and maximum score of 20) with a higher score indicating the possibility of underlying anxiety and greater than 9 indicating the possibility of an underlying anxiety disorder. At the conclusion of the study a reduction or absence of change is expected in the geriatric anxiety score.
Evaluation of dementia stage using the Clinical Dementia Rating Scale (CDR).	12 months (assessed baseline, 6 months and 12 months)	CDR evaluates multiple domains including memory, orientation, judgement and problem solving, home and hobbies, community and personal care using a 5-point scale (0, 0.5, 1, 2, 3, where higher score indicates increasing severity of dementia) from 0 (no dementia) to a maximum of 3 (severe dementia). A 0.5-1 score indicates possible to mild cognitive impairment.
Assessment of plasma neurofilament light chain (NfL) protein levels	12 months (assessed at baseline and every 3 months)	Elevated levels of NfL are suggested to be a biomarker of neurodegeneration and hence changes in this biomarker could reflect pathological changes. Increasing levels of NfL suggest progression or increasing severity of neurodegeneration and cognitive impairment whereas unchanged or decreasing levels of NfL may indicate a stabilisation or mitigation of neurodegeneration.
Evaluation of cognition using the Singapore Modified - Mini Mental State Examination Scores (Cognitive function assessment)	12 months (assessed baseline, 6 months and 12 months)	30 point questionnaire to assess for cognitive function and memory recall, with a minimum score of 0 and maximum of 30; where higher is better. A score of less than 7 may be indicative of cognitive impairment.
Neuropsychological test battery: Rey Auditory Verbal Learning Test (Cognitive function assessment)	12 months (assessed baseline, 6 months and 12 months)	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 the words. 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. A score out of 75 for immediate recall and 30 for secondary and delayed recall, whereby higher indicates better verbal learning and memory.
Neuropsychological assessment battery: Digit Span test (Cognitive function assessments)	12 months (assessed baseline, 6 months and 12 months)	The digit span task is a measure of working memory, based on a person's ability to recall a sequence of numerical digits evaluating short-term and working memory. A maximum score of 16 for forward and 14 for backward where higher indicates score indicates better short-term and working memory and cognitive control.
Neuropsychological assessment battery: Block Design Test (Cognitive function assessment)	12 months (assessed baseline, 6 months and 12 months)	The block design test examines the spatial visualisation ability and motor skills of an individual where the subject is asked to replicate a different design patterns using cubes. Scoring as based on timing and correct pattern with a maximum score of 68 with higher indicating better spatial visualisation.
Neuropsychological assessment battery: Symbol Digit Modality Test scores (Cognitive function assessment)	12 months (assessed baseline, 6 months and 12 months)	The symbol digit modality is a cognitive assessment test for evaluating information processing speed and attention. Increased written and oral symbol score (1 point per correct answer, minimum of 0 and maximum of 100 limited by the test form) over 90 seconds indicates better processing speed.
Evaluation of Geriatric Depression Scale (Neuropsycological assessment)	12 months (assessed baseline, 6 months and 12 months)	The geriatric depression scale is a self-reported assessment to identify depressive symptoms in elderly individuals, through a series of 15 guided questions (with minimum of 0 and maximum score of 15) with a higher score indicating greater severity and greater than 5 indicating the possibility of an underlying depressive syndromes. At the conclusion of the study a reduction or absence of change is expected in the geriatric depression scale.

Trial Locations

Locations (1)

National University Cancer Institute, Singapore; 🇸🇬 Singapore, Singapore