Using Circulating mRNA in Blood as Brain Disorder Biomarkers

Researchers in a Johns Hopkins Children’s Center-led study that used genetic material from human blood and lab-grown brain cells say they have made progress in developing a blood test to identify disease-associated changes in the brain specifically linked to postpartum depression and other psychiatric and neurological disorders. 

The research findings, published recently in Molecular Psychiatry, focused on identifying the “footprints” of brain cell-derived mRNAs in blood circulating outside the brain. These blood extracellular vesicles (EVs) carry brain-specific pieces of mRNA that potentially allow researchers to detect disease-associated changes in gene activity inside the brain.

Leveraging mRNAs as brain health biomarkers

First, using the human placenta as a model, the investigators identified 26 placental mRNAs that are present in maternal blood only during pregnancy and not following birth, proving that mRNAs from specific tissues are found in EVs in circulating blood. Then, using brain organoids, researchers found that EV mRNAs that are released from these brain tissues reflected the changes occurring inside the tissues. 

Sarven Sabunciyan, PhD, an assistant professor of pediatrics at the Johns Hopkins University School of Medicine, and the paper’s senior author, and his team conclude that it is possible to gather biological information about normally inaccessible tissues, such as the placenta and the brain, by examining EV mRNAs circulating in the blood. 

They were able to identify mRNAs that are specifically expressed in the brain using data from the Human Protein Atlas—a Sweden-based database of human proteins in cells, tissues, and organs—and the Genotype-Tissue Expression Project, which has extensively cataloged mRNA levels in human tissues.

Further analysis of those mRNA genetic pathways showed that the brain-specific mRNAs in blood EVs were involved in particular brain functions, and were significantly enriched for genes already associated with brain disorders that involve mood, schizophrenia, epilepsy, and substance abuse. The research team suggests that these mRNAs are likely to be ideal biological markers for identifying such conditions. 

“This is very exciting because right now, there isn’t a blood marker for disorders affecting the brain,” says Lena Smirnova, PhD, an assistant professor in the Department of Environmental Health and Engineering at the Johns Hopkins Bloomberg School of Public Health and co-author of the paper. “Essentially, these conditions are diagnosed by clinical interviews between patients and [healthcare] providers.”  

Insights into postpartum depression and mental health disorders

Researchers also discovered 13 brain-specific mRNAs in the blood that were found to be associated with postpartum depression. To determine the extent to which blood EV mRNAs reflect transcription in the brain, researchers compared mRNAs isolated from cells and EVs in a brain organoid model. They found that although cellular and extracellular mRNA levels are not identical, they do correlate, and it is possible to extrapolate cellular expression changes in the brain via EV mRNA levels.   

“The goal is to develop a simple blood test to detect changes such as higher or lower levels of blood EV mRNAs directly linked to changes in the brain associated with mental disorders without having access to the brain itself,” says Sabunciyan.

Sabunciyan adds, “Eventually, the availability of such blood tests could enable detection of early signs of mental health emergencies, such as suicidal behavior. The ability to identify patients who are at risk of having a psychiatric episode would enable the care team to intervene and possibly prevent negative outcomes.” 

In future studies, the team plans to use brain organoids to identify similar biomarkers to develop tests for autism spectrum disorder.  The researchers caution that the differences identified for depression may be linked only to postpartum depression because the study was conducted using samples only from female participants.

- This press release was originally published on the Johns Hopkins Medicine website