A new biomarker may help diagnose late-life depression before it sets in

June 8, 2021

Late-life depression can be linked to higher levels of cell-free mitochondrial DNA in the bloodstream. (Unsplash/Christian Langballe)

Canadian researchers have discovered an elusive marker that links late-life depression to oxidative stress, the same stress that can occur from a range of influences, from smoking or alcohol intake to a major depressive episode.

By linking late-life depression to higher levels of cell-free mitochondrial DNA circulating in patients' bloodstreams, researchers may now be able to diagnose major depression earlier — avoiding the onset of later complications — as well as develop new drugs that target the mitochondrial activity that generates this type of DNA and is associated with oxidative stress.

"I hope to bring new knowledge and innovation that could lead in the future to better diagnosis for mental illnesses, and also new treatment," said co-lead author Vanessa Gonçalves, a scientist at the Centre for Addiction and Mental Health in Toronto and an assistant professor at the University of Toronto. Her study documenting the finding was published May 8 in the Journal of Psychiatric Research.

According to Gonçalves, the study was inspired by a lack of biomarkers, which are measurable signs or indicators of disease, that could help diagnose mental illness. In this case, the researchers identified higher levels of circulating cell-free mitochondrial DNA, or ccf-mtDNA, as a reliable biomarker for depression in older adults. Under duress, cells emit this form of DNA into the bloodstream. 

Depression is especially dangerous in older adults, Gonçalves noted, because it fosters worse health outcomes and increases overall mortality. 

To find out how oxidative stress might manifest in depressed patients, Gonçalves and her colleagues enlisted 32 participants who were age 68, on average, and suffered from depression, as well as 21 controls who did not report any depression and were 70 years old, on average. The study excluded people with a history of alcohol or drug abuse.

The researchers then took blood samples from all of the subjects and extracted plasma from each of the samples, from which they could quantify the amount of circulating cell-free mitochondrial DNA.

The team found that the amount of this biomarker was much higher in the depressed patients than in the controls, too high to have been caused by chance, according to Gonçalves. Also, the team did not find a significant correlation between smoking and ccf-mtDNA.

But the results did show a clear association between ccf-mtDNA and depression in older adults, offering new evidence that this type of DNA can be a marker of cellular stress, due to malfunctioning mitochondria, in a major depressive episode.

Even though Gonçalves and her colleagues were able to correlate ccf-mtDNA and oxidative stress with late-life depression, scientists still don't entirely understand the mechanism behind this relationship. According to Gonçalves, oxidative stress creates more reactive oxygen species, or ROS, which are highly reactive byproducts of the aerobic metabolism of oxygen. 

The additional ROS in the body from oxidative stress, in addition to damaging mitochondria, can disrupt homeostasis between the hypothalamus, pituitary gland and adrenal glands, all parts of the endocrine system. Mitochondrial damage has been implicated in depression in younger populations as well, according to Gonçalves.

In future research, Gonçalves plans to correlate her findings with other inflammatory and oxidative stress parameters and will continue efforts to validate these current findings in larger sample sizes. She says this work is important because of "the opportunity that the results hold to make a difference for those suffering with mental illnesses."

The study, "Increased levels of circulating cell-free mtDNA in plasma of late life depression subjects," published May 8 in the Journal of Psychiatric Research, was authored by Vanessa F. Gonçalves, James L. Kennedy and Breno Diniz, Centre for Addiction and Mental Health and University of Toronto; and Ana Paula Mendes-Silva, Emiko Koyama and Erica Viera, Centre for Addiction and Mental Health.

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