A comprehensive nontargeted metabolomics analysis has revealed previously unknown classes of disease-linked metabolites in whole blood samples from dementia patients, which may have significant therapeutic implications for managing the untreatable common cognitive disorder.
In particular, inhibiting some of these metabolic biomarkers or supplementing others may provide dementia treatments, the Japanese authors reported in the September 7, 2021, online issue of Proceedings of the National Academy of Sciences.
"This is the most comprehensive metabolomics analysis performed to date and differs from other such analyses, which... remain scarce," said study leader Mitsuhiro Yanagida, a professor in the G0 Cell Unit at Okinawa Institute of Science and Technology (OIST) Graduate University.
Most notably, "we used whole blood for the metabolomics analyses, whereas most such studies use plasma, despite almost half of metabolites being found in red blood cells (RBCs)," Yanagida told BioWorld Science.
A result of neuronal damage, dementia is characterized by marked deterioration in memory, thought, behavior and performance of daily activities.
Alzheimer's disease (AD) is the most common global cause of dementia, which usually presents in individuals aged 65 years or over. Approximately 6% of those have dementia, representing a significant health and economic burden, especially in developed countries.
While mental and physical exercise, and avoiding risk factors such as obesity may reduce dementia risk, as yet mechanistic causes and definitive treatments have remained elusive, prompting the new metabolomics analysis.
Although more labor-intensive than a targeted study, thorough nontargeted metabolomics analysis can identify diagnostic compounds missed by targeted analysis and clarify metabolic changes in dementia.
However, "the main reason for using the nontargeted method is to eliminate any bias regarding metabolites of which the abundance is altered by dementia," said Yanagida.
Moreover, little is known about RBC metabolomics in relation to diseases, despite RBCs accounting for about 40% of all blood metabolites, which could also provide critical information on health and disease.
In the new PNAS study, Yananiga's group, in collaboration with National Hospital Organization Ryukyu Hospital, performed whole-blood metabolite profiling of dementia patients using liquid chromatography-mass spectroscopy (LC-MS) to reveal metabolic compounds related to dementia.
The research team identified 33 biomarker metabolites that they classified into five groups, A to E, which were shown to differ significantly in dementia patients, compared with controls.
"For controls, we used frail elder individuals whose cognitive ability was slightly impaired, who turned out to be excellent in this respect," explained Yanagida.
"We have also been investigating metabolomics in frail patients with normal cognitive ability, who were also found to have cognitive markers for dementia," he noted.
However, "in the current study, all of the subjects were diagnosed with dementia, so the majority of the markers are novel, although some, notably ergothioneine [see below], have been linked to dementia in other studies."
The biomarkers were then validated by principal component analysis (PCA), correlation, and heat-map analyses, to confirm they were involved in dementia development.
Seven group A metabolites, including quinolinic acid, kynurenine and indoxyl-sulfate, were found to be increased in dementia patients, suggesting these compounds may act as central nervous system (CNS) neurotoxins.
"These group A metabolites are all considered to be neurotoxic and in future we may investigate their inhibition in animal models of AD," said Yanagida.
Concentrations of the remaining 26 compounds, groups B to E, were all found to be significantly lower in dementia patients versus controls, possibly causing a loss of support or protection of the brain in dementia.
"We may also investigate those molecules in groups B to E for their dementia curative potential in animal models of AD," he said.
Six group B metabolites, which are normally enriched in the RBCs of healthy subjects, were shown to contain trimethylated ammonium moieties.
These metabolites were found to include ergothioneine and related compounds that have been little investigated as dementia markers, validating the examination of RBC metabolites.
A potent antioxidant, ergothioneine is significantly decreased in various cognition-related disorders, including mild cognitive impairment.
"We would like to better understand these compounds regarding their putative ability to 'protect' the CNS in the future," said Yanagida.
Meanwhile, "the role of ergothioneine in this regard has been the subject of considerable debate, with a collection of letters being scheduled for publication in the Federation of the European Biochemical Societies Journal in the near future."
Group C compounds were also shown to include oxidoreductants normally abundant in RBCs, including nicotinamide adenine dinucleotide phosphate (NADP+), glutathione, adenosine triphosphate (ATP), pantothenate, S-adenosyl-methionine and gluconate.
The decreased levels of these oxidoreductants demonstrated in dementia patients may also contribute to depressed brain function.
The 12 group D plasma compounds included amino acids, glycerol-phosphocholine, dodecanoyl-carnitine, and 2-hydroxybutyrate, which normally protect the brain, but that protection may be impaired by their diminution in dementia.
Together, these findings indicate that patient interventions for cognitive diseases involving these dementia metabolomic markers may be achieved either by inhibiting group A compounds or by supplementing group B to E compounds.
Looking ahead, "subject to availability of funding at OIST, we would like to continue this research, which is now at a fascinating stage," said Yanagichi. "We would also be interested in further investigating the role of RBC metabolites in dementia, which remains controversial."