Whole blood metabolomics of dementia patients reveal classes of disease-linked metabolites

Abstract

Dementia is caused by factors that damage neurons. We quantified small molecular markers in whole blood of dementia patients, using non-targeted liquid chromatography-mass spectroscopy (LC-MS). Thirty-three metabolites, classified into 5 groups (A-E), differed significantly in dementia patients, compared with healthy elderly subjects. Seven Group A metabolites present in plasma, including quinolinic acid, kynurenine, and indoxyl-sulfate, increased. Possibly they act as neurotoxins in the central nervous system (CNS). The remaining 26 compounds (Groups B-E) decreased, possibly causing a loss of support or protection of the brain in dementia. Six Group B metabolites, normally enriched in red blood cells (RBCs) of healthy subjects, all contain trimethylated ammonium moieties. These metabolites include ergothioneine and structurally related compounds have scarcely been investigated as dementia markers, validating the examination of RBC metabolites. Ergothioneine, a potent anti-oxidant, is significantly decreased in various cognition-related disorders, such as mild cognitive impairment and frailty. Group C compounds, also include some oxidoreductants and are normally abundant in RBCs (NADP+, glutathione, ATP, pantothenate, S-adenosyl-methionine, and gluconate). Their decreased levels in dementia patients may also contribute to depressed brain function. Groups D (12) contains plasma compounds, such as amino acids, glycerophosphocholine, dodecanoyl-carnitine, 2-hydroxybutyrate, which normally protect the brain, but their diminution in dementia may reduce that protection. Seven Group D compounds have been identified previously as dementia markers. Group B-E compounds may be critical to maintain the CNS by acting directly or indirectly. How RBC metabolites act in the CNS and why they diminish so significantly in dementia remain to be determined. Significance StatementDementia is a slowly progressing, chronic, and usually irreversible decline in cognitive function. Mechanistic causes and definitive treatments remain elusive. Using comprehensive metabolomics, we identified 5 groups of metabolites (A-E), 21 of which are novel, possibly useful for diagnosis and therapy of forms of dementia, such as Alzheimers disease. Seven Group A compounds may act as neurotoxins, whereas Group B-E compounds may protect the CNS against oxidative stress, maintain energy reserves, supply nutrients and neuroprotective factors. Five metabolites, ergothioneine, S-methyl-ergothioneine, trimethyl-histidine, methionine, and tryptophan identified in this study overlap with those reported for frailty. Interventions for cognitive diseases involving these dementia metabolomic markers may be accomplished either by inhibiting Group A compounds or by supplementing Group B-E compounds in patients.