期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：37
DOI：10.1073/pnas.2022857118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Dementia is a slowly progressing, chronic, and usually irreversible decline in cognitive function. Mechanistic causes and definitive treatments remain elusive. Using comprehensive metabolomics, we identified five groups of 33 metabolites (A to E), 13 of them previously reported, possibly useful for diagnosis and therapy of forms of dementia, such as Alzheimer’s disease. Seven A compounds may act as neurotoxins, whereas B to E compounds may protect the nervous system against oxidative stress, maintain energy reserves, supply nutrients and neuroprotective factors. Five metabolites, ergothioneine,
S-methyl-ergothioneine, trimethyl-histidine, methionine, and tryptophan, overlap with those reported for frailty. Interventions for cognitive diseases involving these dementia metabolomic markers may be accomplished either by inhibiting A compounds or by supplementing B to E compounds in patients.
Dementia is caused by factors that damage neurons. We quantified small molecular markers in whole blood of dementia patients, using nontargeted liquid chromatography–mass spectroscopy (LC-MS). Thirty-three metabolites, classified into five groups (A to E), differed significantly in dementia patients, compared with healthy elderly subjects. Seven 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 (B to E) decreased, possibly causing a loss of support or protection of the brain in dementia. Six B metabolites, normally enriched in red blood cells (RBCs), all contain trimethylated ammonium moieties. These metabolites include ergothioneine and structurally related compounds that have scarcely been investigated as dementia markers, validating the examination of RBC metabolites. Ergothioneine, a potent antioxidant, is significantly decreased in various cognition-related disorders, such as mild cognitive impairment and frailty. C compounds also include some oxidoreductants and are normally abundant in RBCs (NADP
+, glutathione, adenosine triphosphate, pantothenate,
S-adenosyl-methionine, and gluconate). Their decreased levels in dementia patients may also contribute to depressed brain function. Twelve D metabolites contains plasma compounds, such as amino acids, glycerophosphocholine, dodecanoyl-carnitine, and 2-hydroxybutyrate, which normally protect the brain, but their diminution in dementia may reduce that protection. Seven D compounds have been identified previously as dementia markers. B to 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 significantly in dementia remain to be determined.
