A new study claims to have discovered 33 metabolites that are linked with dementia. The finding may provide the foundation for a possible future cure for this disease currently afflicting millions worldwide. (Above: Amyloid plaques are proteins that clump together between the brain cells of Alzheimer's disease patients.)

Dementia, a general term for the impaired ability to remember, think, or make decisions that interferes with everyday activities. There are many diseases that fall under this umbrella term, but as a whole it is the most serious and severe of all diseases associated with the geriatric community. Currently, an estimated 55 million people worldwide are afflicted with this disease. 

The study revealed 33 metabolic substances that could play a role in those who suffer from dementia. The study found that diseased individuals had higher levels of these metabolites as opposed to the elderly with no previous health conditions. Some of these metabolites discovered are believed to be neurotoxic, and the causes of neuron depletion in patients diagnosed with dementia. These findings may aid and improve diagnosis and treatment of the ailment in the future. 

Dr. Takayuki Teruya, a scientist in the G0 Cell Unit at the Okinawa Institute of Science and Technology Graduate University (OIST) said recently, "Metabolites are chemical substances produced by vital chemical reactions that occur within cells and tissues. 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." 

The research team associated with this study collected blood samples from 8 patients with dementia, along with 8 healthy, elderly patients. Their blood was then analyzed to determine if any of these 16 test patients had the signal metabolic compounds in their blood. Of the 33 metabolites originally discovered, 26 known to be neuroprotectors aiding to shield neurons from free radicals, improve energy reserve efficiency, and provide nutrition were found at lower levels in those diagnosed with dementia. Along with that, 7 metabolites known to be toxic to neurons, were found at increased levels in those with dementia. 

Scientists involved in the study measured 124 different metabolite levels in whole blood and found that, of those 124 metabolites, 33 associated with dementia, could be split into 5 different sub-groups. The aforementioned 7 metabolites in increased levels in patients with dementia could be found in the blood plasma and belonged to the "A" sub-group of metabolites. These substances are known to have toxic effects on the central nervous system. 

This study provided experts with an insight to the diseased human mind and potential avenues for curing the worldwide ailment of dementia. Although a long road lies ahead for these researchers and all involved in this race for a cure, the information found in this study lays a foundation ready to build upon for future generations of researchers in the neuromedical field. 

Professor Mitsuhiro Uanagida, leader of the G0 Cell Unit at OIST, concluded, "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."

The study was published in PNAS, on September 10th, 2021.

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.

Whole blood metabolomics of dementia patients reveal classes of disease-linked metabolites Takayuki Teruya, Yung-Ju Chen, Hiroshi Kondoh, Yasuhide Fukuji, Mitsuhiro Yanagida bioRxiv 2021.06.22.449525; doi: https://doi.org/10.1101/2021.06.22.449525

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