A study led by researchers at the Johns Hopkins Children’s Center utilized genetic material from human blood and lab-grown brain cells to make advances in developing a blood test to identify disease-related changes in the brain. Specifically, these changes are related to postpartum depression and other psychiatric disorders, as well as neurological disorders.
The research, published in Molecular Psychiatry on January 11, focused on identifying the „footprints“ of brain cell-derived mRNAs in the blood that circulates outside the brain. These extracellular blood vessels contain brain-specific parts of genetic material, which may allow researchers to identify disease-related changes in brain gene activity.
Extracellular vesicles (EVs), fatty sacs containing genetic material essential for cell communication, carry messenger RNA (mRNA) and are released by every tissue in the body, including the brain.
The new research was inspired by the results of a study published in September 2022, in which scientists at Johns Hopkins Medicine discovered that EV communication is altered in pregnant women who develop postpartum depression after giving birth.
„We have detected placenta-specific EVs only during pregnancy and not after birth. This was evidence of the concept that we can identify EVs originating from a specific tissue or organ.“
Sarven Sabunciyan, Ph.D., Assistant Professor of Pediatrics at the Johns Hopkins University School of Medicine and senior author of the article
Initially, the researchers identified 26 placenta mRNAs that are present only during pregnancy and not after birth in maternal blood, proving that mRNAs from specific tissues are found in EVs in circulating blood. Using laboratory-grown human brain tissue obtained from stem cells (brain organoids), the researchers then discovered that EV mRNAs released from this brain tissue reflect changes that occur in the tissue. Sabunciyan and his team concluded that it is possible to collect biological information about normally inaccessible tissues such as the placenta and the brain by examining circulating EV mRNAs in the blood.
Using data from the Human Protein Atlas and the Genotype-Tissue Expression Project, they were able to identify mRNAs specifically expressed in the brain and analyze their involvement in certain brain functions. This revealed that brain-specific mRNAs in blood EVs were significantly associated with genes already linked to brain disorders such as mood swings, schizophrenia, epilepsy, and substance abuse.
The research team says this analysis suggests that these mRNAs are likely ideal biological markers for identifying such disorders.
„This is very exciting, as there are currently no blood markers for brain-related diseases,“ said Lena Smirnova, Ph.D., Assistant Professor at the Department of Environmental Health and Engineering at the Johns Hopkins Bloomberg School of Public Health and co-author of the article. „Essentially, these diseases are diagnosed through clinical interviews between patients and providers.“
The researchers also discovered 13 brain-specific mRNAs in blood related to postpartum depression. To determine the extent to which EV mRNAs in the blood reflect transcription in the brain, the researchers compared mRNAs isolated from cells and EVs in a brain organoid model. They found that while cellular and extracellular mRNA levels are not identical, they do correlate, suggesting it is possible to extrapolate cellular expression changes in the brain through EV mRNA levels.
The goal is to develop a simple blood test to recognize changes such as higher or lower levels of EV mRNAs in the blood directly related to changes in the brain associated with mental disorders, without direct access to the brain itself, Sabunciyan said.
Ultimately, having such blood tests available could enable the early detection of warning signs for mental health emergencies, such as suicidal behavior. Identifying patients at risk of a psychiatric episode would allow the care team to intervene and potentially prevent negative outcomes,“ Sabunciyan added.
In future studies, they plan to use laboratory-grown brain samples to identify similar biomarkers and develop tests for autism spectrum disorders. The researchers cautioned that the differences observed in relation to depression may be specific to postpartum depression, as the study was conducted only with female participants.
In addition to Sabunciyan and Smirnova, the authors include Sergio Modafferi and Charlotte Schlett from Johns Hopkins; Lauren Osborne from Weill Cornell Medicine; and Jennifer Payne from the University of Virginia.
The study was funded by grants from the National Institutes of Health under grant numbers NIH-NIMH R01 MH112704, NIH-NIMH 1K23 MH110607 and R01ES034554.
Smirnova, L., Modafferi, S., Schlett, C., Osborne, LM, Payne, JL, & Sabunciyan, S. (2024). Extracellular vesicles carrying brain-specific mRNAs are potential biomarkers for detecting gene expression changes in the female brain. Molecular Psychiatry. doi.org/10.1038/s41380-023-02384-6.