Association of ergothioneine with neurodegeneration and cerebrovascular disease in cognitive impairment and dementia

Abstract Background Ergothioneine (ET) is a dietary amino‐thione with strong antioxidant properties and therapeutic potential for neurodegenerative and vascular diseases (Halliwell et al., 2018; Smith et al., 2020). Decreased blood concentrations of ET have been found in patients with mild cognitive impairment (Cheah et al., 2016), but its status in neurodegenerative and vascular dementias are currently unclear. We thus investigated the association of plasma ET levels with (1) cognitive impairment and dementia, (2) cerebrovascular disease (CeVD), namely white matter hyperintensities (WMH), cortical infarcts and lacunes and (3) brain atrophy. Method A cross‐sectional study was conducted in a total of 496 participants in an ongoing longitudinal study, including 88 subjects with no cognitive impairment (NCI), 201 subjects with cognitive impairment but no dementia (CIND), 207 dementia patients of whom 160 had Alzheimer’s Disease and 47 vascular dementia (VaD). All subjects underwent collection of blood samples, neuropsychological assessment, and neuroimaging. Plasma ET levels were measured with a high sensitivity liquid chromatography tandem‐mass spectrometry (LC‐MS/MS) method. Result Plasma ET concentrations were lowest in dementia (p<0.001 vs. NCI and CIND), with intermediate levels in CIND (p<0.001 vs. NCI). In multivariate analyses, lower levels of ET were significantly associated with CIND (OR, 0.20; 95% CI, 0.07–0.56; p<0.01) and dementia (OR, 0.06; 95% CI, 0.02–0.20; p<0.001) after adjustment for demographics and risk factors. There was a positive correlation between plasma ET and MMSE scores (r=0.341, p<0.001). Lower ET levels were also strongly associated with WMH (OR, 0.44; 95% CI, 0.123–0.85); p<0.01) and brain atrophy markers (cortical atrophy: OR, 0.42; 95% CI, 0.20–0.92; central atrophy: OR, 0.46; 95% CI, 0.22–0.93; medial temporal atrophy: OR, 0.45; 95% CI, 0.24–0.99, p<0.05 for all). Conclusion The incremental decreases in ET levels along the clinical continuum suggest that ET may be associated with disease severity and is a potential biomarker for early detection of cognitive impairment. Deficiency of ET may contribute towards neurodegeneration‐ and CeVD‐associated cognitive impairments by exacerbating the deleterious effects of oxidative stress in these conditions.