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Neurodegenerative diseases 

The brain’s timepiece

Compounds found in blood may indicate degree of brain aging

NELSON PROVAZIA group of Brazilian researchers may have found a simple and minimally invasive way to measure the degree of brain aging. In studies with rodents and humans, they observed that the level of three compounds found in blood cells may reflect the health of brain cells. If tests that remain to be conducted prove successful, it is expected that a way will be discovered to identify neurodegenerative diseases like Alzheimer’s and Parkinson’s at very early stages, before clinical signs appear.

“We’ve found a set of compounds in the blood of people with these diseases that indicate overproduction of toxic substances in the brain,” explains pharmacologist Cristoforo Scavone, head of the Molecular Neuropharmacology Laboratory at the Institute of Biomedical Sciences of the University of São Paulo (USP) and one of the study coordinators.

For over a decade, Scavone, together with pharmacologists Tania Marcourakis, of USP’s School of Pharmaceutical Sciences, and Elisa Kawamoto, currently a researcher at the National Institutes of Health in the United States, have been searching for compounds that serve as biomarkers of brain aging and of the diseases that usually attack the brain as people grow older. According to some theories, the body ages – and dies – because its cells lose their ability to recover from the constant damage caused by free radicals. In line with this reasoning, diseases like Alzheimer’s are a consequence of the accelerated aging of brain cells that have lost their ability to fight off the free radicals produced during life-sustaining chemical reactions, especially cellular respiration, which converts glucose into energy.

Marcourakis, Kawamoto, and Scavone compared the levels of compounds produced by blood and brain cells and identified three that may reflect the ability to deal with free radicals. All three compounds have complicated names – cyclic guanosine monophosphate (cyclic GMP), nitric oxide synthase (NOS), and thiobarbituric acid reactive substances (TBARS) – and their levels vary as the body ages.

Cyclic GMP takes part in chemical reactions that help to eliminate free radicals. As the years go by, its levels drop in both the brain cells and the platelets (cells that play a key role in blood clotting), as researchers have observed through periodic measurement of rats from birth through 24 months of age – which is about 85 in human years. The opposite occurred with levels of NOS, an enzyme involved in the production of free radicals, and also of TBARS, a compound that results from damage to the cell membrane. According to a study published in the journal Age early this year, the amount of NOS in platelets and of TBARS in erythrocytes – the blood cells that carry oxygen – increased by a ratio similar to their increase in brain cells.

072-073_Envelhecimento Cerebral_200Alzheimer’s
Some of the changes recently noted in rodents had already been identified by researchers in people with Alzheimer’s. Early last decade, Kawamoto, Marcourakis, and Scavone, in partnership with neurologist Ricardo Nitrini, also of USP, analyzed NOS levels in the brains of Alzheimer’s sufferers and ascertained that they were higher than in people without the disease. “The picture we found of oxidative stress [overproduction of free radicals] in patients suggests that there is a biochemical imbalance, in comparison with healthy aging,” says Kawamoto.

Researchers then repeated tests with rats ranging in age from 4 to 24 months and learned that the older the animal, the greater the production of NOS, an enzyme associated with the production of nitric oxide, which is a compound essential for life that acts as a neurotransmitter in the central nervous system and that, when in excess, kills cells by generating free radicals (see Pesquisa FAPESP nº 161).

In the opinion of neuroscientist Luiz Eugênio Mello, of the Federal University of São Paulo (Unifesp), the three compounds seem to work like markers of brain aging. But further experiments must be done to discover whether they really enable identification of neurodegenerative diseases before clinical signs appear. “Tests are needed on healthy elderly individuals and on elderly individuals with neurodegenerative diseases to confirm whether there really is a difference in the levels of these markers,” Mello says. Even if such differences are confirmed, it must be determined whether they are the result of aging and neurodegenerative illnesses or of environmental factors. “What influence does smoking, pollution, and other factors have?” Mello asks.

Scavone agrees with this analysis and says that one of the next steps will be to investigate the influence of environmental factors. “Maybe physical exercise or an intellectually active life could help the brain preserve the recovery capacity it has when we’re young,” he speculates.

It is not yet known whether the biochemical imbalance observed with Alzheimer’s also occurs in illnesses like Parkinson’s. “Neurodegenerative diseases share basic physiopathological mechanisms, which are oxidative stress and excitotoxicity,” says Marcourakis. “That’s why we might find similar results.” In an article published in the Journal of Alzheimer’s Disease in 2011, Marcourakis and collaborators showed that it is possible to identify increased oxidative stress in blood samples from people with mild cognitive impairment, an intermediary stage between normal aging and Alzheimer’s.

“If these three compounds are validated as markers of brain aging, it’s possible to imagine that they might lead to a test with clinical application,” Scavone says. A blood test for early identification of problems related to brain aging will be valuable in a world that is growing older. The World Health Organization estimates that in 2010, 35 million people were living with some form of dementia – 70% of them with Alzheimer’s. This number is expected to jump to 65.7 million by 2030.

Projects
1.
Assessment of oxidative stress in platelets of patients with Alzheimer’s disease (nº 1999/09454-5); Grant mechanism: Regular Line of Research Project Award; Coordinator: Tania Marcourakis – School of Pharmaceutical Sciences/USP. Investment: R$ 114,459.68 (FAPESP).
2. Aging and Alzheimer’s disease: continuous processes? The effect of anticholinesterases and antioxidants (nº 2004/10205-0); Grant mechanism: Regular Line of Research Project Award; Coordinator: Tania Marcourakis – School of Pharmaceutical Sciences/USP; Investment: R$ 55,077.62 (FAPESP)

Scientific articles
KAWAMOTO, E. M. et al. Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system. Age. 26 Jan. 2012.
TORRES, L.L. et al. Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer’s disease. Journal of Alzheimer’s Disease. v. 26(1), pp. 59-68. 2011.