Researchers from the Hebrew University of Jerusalem and Jerusalem’s Shaare Zedek Medical Center have discovered that brain cells die in a psychotic attack and a simple blood test could make it possible to predict such an event and treat it.
Groundbreaking biological marker for psychosis
The groundbreaking discovery allowed researchers to identify significant brain damage during a psychotic attack, such as in a schizophrenic episode, when they compared the patients to healthy subjects. This is the first time a biological marker for psychosis has ever been found. The test could lead to early detection, diagnosis, early intervention and appropriate treatment for schizophrenia.
This first brain research of its kind was led by Dr. Asael Lubotzky, a senior pediatrician in Shaare Zedek’s Neuropediatric Unit, as part of a doctoral dissertation supervised by two researchers from Hebrew University’s Faculty of Medicine – Prof. Yuval Dor and Prof. Ruth Shemer – and in collaboration with psychiatrists from the Eitanim Mental Health Center – Dr. Ilana Pelov and Prof. Yoav Cohen.
The article has just been published in the journal eLife under the title “Elevated brain-derived cell-free DNA among patients with first psychotic episode – a proof-of-concept study.”
Helping schizophrenia
Schizophrenia is a common, severe and debilitating psychiatric disorder. Despite extensive research, no biological markers have ever been discovered that can aid in its diagnosis and prediction of its course. This makes early detection and intervention impossible, they wrote.
Psychosis is the first presentation of schizophrenia that usually leads to the diagnosis. Although psychosis typically begins during adolescence and young adulthood, there is a growing amount of data that show underlying biological changes beginning years before symptoms of psychosis. Thus, identifying biomarkers that will allow early diagnosis and therapeutic interventions is of the highest importance.
“Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis [cell death] has been proposed as the underlying mechanism. Cell-free DNA (cfDNA) fragments are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA,” the study’s authors wrote.
“We developed a cocktail of brain-specific DNA methylation markers biochemical process where a DNA base, usually cytosine, is enzymatically methylated at the 5-carbon position. An epigenetic modification associated with gene regulation, DNA methylation is of paramount importance to biological health and disease.”
In the course of life, aging processes, environmental influences and lifestyle factors such as smoking or poor diet induce biochemical changes in the DNA. Frequently, these lead to DNA methylation, a process in which methyl groups are added to particular DNA segments, without changing the DNA sequence. Potential interpretations of these findings include increased brain cell death, disruption of the blood-brain barrier or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.
How was this brain study conducted?
THE JERUSALEM researchers examined dozens of psychiatric patients, 29 of them with a first psychotic attack. Shortly after the attack began, blood samples were taken by Pelov and compared to 31 samples from healthy subjects without psychiatric illness. The clinical findings were collected and analyzed by the two Eitanim doctors.
“In our bodies, there are over 200 different types of cells, and when they die, they release free-flowing DNA segments into the bloodstream. A liquid biopsy is a unique blood test that when analyzed can reveal a lot of information about the origin of the dead cells.”
Dr. Asael Lubotzky
“When we compared the blood tests of patients with a psychotic attack and the samples of healthy people of the same age, we saw a dramatic and statistically significant increase in DNA levels from brain sources in patients with the attack compared to the healthy ones,” recalled Lubotzky.
“In our bodies, there are over 200 different types of cells, and when they die, they release free-flowing DNA segments into the bloodstream. A liquid biopsy is a unique blood test that when analyzed can reveal a lot of information about the origin of the dead cells.”
Until now, there have been no biomarkers for brain damage, so it has not been possible to detect or track psychiatric or brain disease through blood tests. This is other systems in our body, such as enzymes that can show liver damage or cardiac markers that reflect myocardial damage.
“In neurological medicine, we try to treat brain diseases that enable us to understand, even if partially, the mechanisms of brain damage,” Lubotsky said. “The world of mental illness is more obscure, and there is a tremendous effort to try to locate and investigate brain mechanisms that explain the pathologies and psychiatric illnesses.”
"Tremendous potential" for the field
Previous studies have shown that in patients with schizophrenia, magnetic resonance imaging (MRI) scans can show a change in brain volume, a finding that indicates a loss of brain tissue. But until now, it has never been known whether brain damage occurs during a psychotic attack and brain cells die.
“In this study, we were able to trace brain cell damage that occurs at the beginning of the psychotic attack. This discovery has tremendous potential for detecting and monitoring other brain diseases,” the researchers wrote.
Scientifically, the findings have other fascinating explanations besides an increase in brain-cell mortality. For example, the blood-brain barrier is known to prevent certain substances from penetrating the bloodstream into the cerebrospinal fluid and vice versa.
“It is possible that people who have a psychotic attack suffer damage to this system, so there is a leakage of cerebral DNA into the blood, but the issue requires in-depth investigation,” the study said.
Lubotzky was a platoon commander in the Israel Defense Forces’ Golani Brigade. He is the author of the Israeli bestseller From the Wilderness and Lebanon that describes his experiences during the Second Lebanon War. Published in 2008, it became a best-selling book, won critical acclaim and was translated into English in 2015. He was severely wounded in the infamous Battle of Bint Jbeil, when an anti-tank missile hit his vehicle.
The book also documents his struggle through numerous operations and a protracted period of rehabilitation, during which he learned to walk again. As a result of his experiences during his hospitalization, he decided to study medicine, and despite a permanent disability that requires him to walk with crutches, he has since become a Shaare Zedek physician. A second book, Not My Last Journey, documenting the life story of his grandfather – the partisan and Irgun officer Iser Lubotzky, was published in 2017. Dr. Lubotzky was awarded the Leitersdorf Prize for the Arts in 2017.