A 3D view of a subject’s brain ventricles. Photo credit: Millward et al., MDC
It’s not just the heart that has chambers – the brain too. Its four ventricles are connected to the spinal canal and are filled with a clear fluid called cerebrospinal fluid, which removes metabolic waste from the neurons. When the brain becomes inflamed, immune cells also circulate in this fluid. This is the case with diseases such as multiple sclerosis (MS), in which the immune system attacks the body’s own protective layer around axons (nerve fibers) in the brain and spinal cord. This triggers inflammation that ultimately leads to the destruction of neurons.
Usually, the brain’s ventricular volume remains fairly constant. Dr. Sonia Waiczies and her colleagues from the Max Delbrück Center for Molecular Medicine of the Helmholtz Association (MDC) and the Charité-Universitätsmedizin Berlin made a discovery in an MS animal model in 2013: They observed that the ventricular volume increased compared to the course of the disease. When they used an antigen to cause encephalitis (inflammation of the brain) in mice, MRIs clearly showed that the ventricles were expanding. “Everyone thought it was a sign of brain atrophy,” recalls Waiczies.
The swelling goes down again
As the ventricles of the brain get bigger, the brain needs to get smaller. After all, the surrounding skull bone doesn’t let it go anywhere else. Inflammation causes brain tissue damage, but atrophy – meaning a massive loss of brain volume – does not always occur immediately. And if so, the process would be irreversible. “That’s why we carried out a number of other animal experiments and monitored the brain volume over two months,” says the neuroimmunologist and lead author of the current study. About ten days after the encephalitis was triggered, the rodents’ brain ventricles were significantly enlarged. Then, a few days later, they shrank back to normal as the symptoms went away. Just like the patients, they would develop temporary relapses – albeit with milder symptoms than at first – and the ventricles would enlarge again.
Waiczies, who also works as an MR scientist, finds these results quite logical: “For example, if I have an inflamed joint, edema forms and it swells. Once the inflammation subsides, the swelling will also decrease. “The team is interested in the molecular mechanisms behind these changes. But first they wanted to know if their results were clinically relevant.
Archive data confirm new findings
Enlarged cerebral ventricles in people with MS are commonly considered a sign of brain atrophy. A reduction in the size of the ventricles has never been reported in patients. What does this observation mean for MS patients? And can the findings even be transferred from mice to humans? In the current study, the researchers tested this using extensive MRI data sets from MS patients. From 2003 to 2008, they took part in a clinical study at the Charité to test the effectiveness of a new MS drug. “I was involved in the immunological planning and evaluation of this study and knew that the MRI data generated are extensive and robust,” says Waiczies.
The diagnosis of multiple sclerosis is made on the basis of MR images and by analyzing the cerebrospinal fluid obtained by puncturing the spinal cord. Regular scans allow a better prognosis of the course of the disease. In this study, participants received a monthly MRI scan. Now countless images had to be viewed and statistically evaluated. The lead author Dr. Jason Millward, neuroimmunologist at the MDC and Charité and statistics enthusiast, set to work on the new study.
“The key factor was the number of measurements taken over time, which gave us a unique opportunity to see if patients were showing similar trends,” explains Millward. Indeed, it was: “The majority of patients with relapsing-remitting MS had fluctuations in ventricular volume – just as we observed in the mice.” Interestingly, Millward also noted that with changes in ventricular volume, the patients appeared to be in an earlier stage of the disease.
“We are used to observing ventricular enlargement in other neurodegenerative diseases – such as Alzheimer or Parkinson’s disease. In these diseases, however, the ventricles do not expand, but are no longer reversible, ”explains Professor Thoralf Niendorf from the MDC, who also works at the Experimental and Clinical Research Center (ECRC), a joint institution of the MDC and Charité. “Regular monitoring of ventricular volume in MS patients could help distinguish transient fluctuations from progressive brain atrophy.” This would also allow therapies to be better tailored to the individual patient.
Professor Friedemann Paul, clinical neuroimmunologist at the Charité and together with Waiczies and Niendorf, the lead author of the current study, adds: “From a clinical point of view, examining fluctuations in the ventricular volume during routine MRI patient scans could be an interesting approach to monitoring the patient The progress of the disease or immunotherapy. However, this requires us to study even larger cohorts over a longer period of time. Comparing these results with clinical findings – for example, regarding cognition – will also be important. ”
The researchers now want to understand how the “up and down” of the brain ventricles takes place on a molecular level.
Reference: November 5, 2020, JCI Insight.
DOI: 10.1172 / jci.insight.140040
