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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
19
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.
Placebo. Study control (99% microcrystalline cellulose, 1% magnesium stearate)
National University Cancer Institute, Singapore
Singapore, Singapore, Singapore
Demonstrating uptake of ergothioneine following dietary supplementation
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
Time frame: 12 months
Demonstrate safety of oral ergothioneine supplementation
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).
Time frame: 12 months
Evaluating the impact of ergothioneine supplementation to modulate oxidative damage
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.
Time frame: Over 12 months
Evaluate the impact of ergothioneine supplementation to modulate inflammation
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.
Time frame: Over 12 months
Assessment of plasma neurofilament light chain (NfL) protein levels
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.
Time frame: 12 months (assessed at baseline and every 3 months)
Evaluation of cognition using the Singapore Modified - Mini Mental State Examination Scores (Cognitive function assessment)
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Evaluation of dementia stage using the Clinical Dementia Rating Scale (CDR).
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological test battery: Rey Auditory Verbal Learning Test (Cognitive function assessment)
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Digit Span test (Cognitive function assessments)
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Block Design Test (Cognitive function assessment)
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Symbol Digit Modality Test scores (Cognitive function assessment)
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Semantic Verbal Fluency Test (Cognitive function assessment)
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Neuropsychological assessment battery: Colour Trials Test (Cognitive function assessments)
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Evaluation of Geriatric Anxiety Inventory (Neuropsycological assessment)
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
Evaluation of Geriatric Depression Scale (Neuropsycological assessment)
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.
Time frame: 12 months (assessed baseline, 6 months and 12 months)
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