Low plasma ergothioneine levels are associated with neurodegeneration and cerebrovascular disease in dementia

Ergothioneine (ET) is a dietary amino-thione with strong antioxidant and cytoprotective properties and has possible therapeutic potential for neurodegenerative and vascular diseases. Decreased blood concentrations of ET have been found in patients with mild cognitive impairment, but its status in neurodegenerative and vascular dementias is currently unclear. To address this, a cross-sectional study was conducted on 496 participants, consisting of 88 with no cognitive impairment (NCI), 201 with cognitive impairment, no dementia (CIND) as well as 207 with dementia, of whom 160 have Alzheimer's Disease (AD) and 47 have vascular dementia. All subjects underwent blood-draw, neuropsychological assessments, as well as neuroimaging assessments of cerebrovascular diseases (CeVD) and brain atrophy. Plasma ET as well as its metabolite l-hercynine were measured using high sensitivity liquid chromatography tandem-mass spectrometry (LC-MS/MS). Plasma ET concentrations were lowest in dementia (p < 0.001 vs. NCI and CIND), with intermediate levels in CIND (p < 0.001 vs. NCI). A significant increase in l-hercynine to ET ratio was also observed in dementia (p < 0.01 vs. NCI). In multivariate models adjusted for demographic and vascular risk factors, lower levels of ET were significantly associated with dementia both with or without CeVD, while ET associations with CIND were significant only in the presence of CeVD. Furthermore, lower ET levels were also associated with white matter hyperintensities and brain atrophy markers (reduced global cortical thickness and hippocampal volumes). The incremental decreases in ET levels along the CIND-dementia clinical continuum suggest that low levels of ET are associated with disease severity and could be a potential biomarker for cognitive impairment. Deficiency of ET may contribute towards neurodegeneration- and CeVD-associated cognitive impairments, possibly via the exacerbation of oxidative stress in these conditions.