Summary: Researchers identified 33 metabolic compounds in blood samples that differed between those with dementia and cognitively healthy older adults. 7 of the metabolites were elevated in dementia patients, while 26 were at lower levels compared to samples of those without dementia. Elevating levels of those metabolites could have a neuroprotective effect against dementia.
Scientists in Japan have identified metabolic compounds within the blood that are associated with dementia.
The study revealed that the levels of 33 metabolites differed in patients with dementia, compared to elderly people with no existing health conditions. Their findings, published this week in PNAS, could one day aid diagnosis and treatment of dementia.
“Metabolites are chemical substances produced by vital chemical reactions that occur within cells and tissues,” said first author Dr. Takayuki Teruya, who works in the G0 Cell Unit at the Okinawa Institute of Science and Technology Graduate University (OIST). “Our body normally keeps these levels in balance, but as we age and if we develop diseases like dementia, these levels can fluctuate and change.”
Dementia is not just a single disease, but a general term used to describe a set of symptoms, including a slow but typically irreversible decline in the ability to remember, think, make decisions or perform day-to-day activities. Of all aging-associated diseases, dementia is one of the most serious, not only for the patients and their family but for society as a whole, with an estimated 55 million people living with the disease worldwide.
While scientists know that dementia is caused by damage to nerves, the exact cause of this damage, and methods as to how it can be detected and treated have remained elusive.
In the study, the research team analyzed samples of blood collected from eight patients with dementia, as well as eight healthy elderly people. They also collected samples from eight healthy young people to use as a reference. Unlike most studies analyzing blood metabolites, this research included compounds found within red blood cells.
“Blood cells are difficult to handle because they undergo metabolic changes if left untreated even for a short period of time,” explained Dr. Teruya.
However, the research team recently developed a way to stabilize metabolites in red blood cells, allowing them to examine for the first time the relationship between red blood cell activity and dementia.
The scientists measured the levels of 124 different metabolites in whole blood and found that 33 metabolites, split into 5 different sub-groups, correlated with dementia. Seven of these compounds increased in dementia patients, whilst 26 of these compounds showed a decrease in levels. 20, including nine that were abundant in red blood cells, of these compounds had not previously been linked to dementia.
“Identification of these compounds means that we are one step closer to being able to molecularly diagnose dementia,” said senior author of the study, Professor Mitsuhiro Yanagida, who leads the G0 Cell Unit at OIST.
The seven metabolites that showed increased levels in patients with dementia were found within the blood plasma and belonged to sub-group A of metabolites. Importantly, some of these compounds are believed to have toxic effects on the central nervous system.
“It’s still too early to say, but it could suggest a possible mechanistic cause of dementia as these compounds may lead to impairment of the brain,” said Prof. Yanagida.
The research team plans to test this idea in the next steps of their research, by seeing if increases in these metabolites can induce dementia in animal models, like mice.
The remaining 26 compounds that decreased in patients with dementia, compared to healthy elderly people, belonged to four other metabolite sub-groups, B-E.
Six metabolites that decreased in dementia patients were classified into sub-group B, due to their similar structure. These metabolic compounds are antioxidants, which protect cells and tissues by reducing damage caused by free radicals – unstable molecules produced by chemical reactions in cells. The researchers found that these antioxidant compounds derived from food were highly abundant in red blood cells of healthy elderly people.
“It could be that red blood cells deliver not only oxygen but also crucial metabolites that protect the nervous system from damage,” said Dr. Teruya.
The remaining sub-groups contain compounds that the researchers believe play a role in supplying nutrients, maintaining energy reserves and protecting neurons from damage.
“In the future, we hope to start some intervention studies, either by supplementing dementia patients with metabolic compounds in sub-groups B-E, or by inhibiting the neurotoxins from sub-group A, to see if that can slow, prevent, or even reverse symptoms of dementia,” said Prof. Yanagida.
Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites
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.