Monitoring Fluctuations in Brain Volume May Help Track RRMS Disease Progression

Monitoring Fluctuations in Brain Volume May Help Track RRMS Disease Progression
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The brain volume of people with relapsing-remitting multiple sclerosis (RRMS) undergoes a dynamic cycle of enlargement and contractions, a new study shows. Patients with a lower volume (contractions) had less severe MS and a shorter disease duration, the study found.

Overall, these findings suggest that frequent monitoring of the brain’s volume using MRI scans could help to track the course of the disease and a patient’s response to immune therapies.

The findings were described in “Transient enlargement of brain ventricles during relapsing-remitting multiple sclerosis and experimental autoimmune encephalomyelitis,” a study published in the journal JCI Insight.

The brain has a network of communicating cavities — called ventricles — which are filled with a clear liquid known as the cerebrospinal fluid (CSF). The CSF bathes the central nervous system (CNS), composed of the brain and spinal cord, and removes the metabolic waste produced by neurons.

Enlargement of the brain’s ventricles volume is linked with neurodegeneration and shrinkage (atrophy) of the brain. While this occurs during the course of normal aging, in MS the expansion is more rapid.

Researchers at the lab of Sonia Waiczies, PhD, at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and at the Charité – Universitätsmedizin Berlin, both in Germany, had previously shown that in a mouse model of MS — called experimental autoimmune encephalomyelitis or EAE — there was a marked enlargement of the brain ventricles at early disease stages. They saw that after triggering encephalitis, or inflammation of the brain, the ventricles expanded, as shown by MRI.

“Everyone thought it was a sign of brain atrophy,” Waiczies, a neuroimmunologist and the study’s senior author, said in a press release.

However, whether this was linked to inflammation or neurodegeneration remained unknown. To answer this, the researchers decided to investigate how the volume of the ventricles changed over time in MS, using MRI.

“We conducted a series of further animal experiments, and monitored the brain volumes over two months,” Waiczies said.

A marked increase of ventricles volume (VV) was seen by the researchers soon after they triggered encephalitis. By day eight after the encephalitis induction, the VV increased by a mean of 130.8%; the increase peaked at 160.7% at day 11.

By day 15, the volume began to decrease and by day 22 VV returned to normal.

The lab said Waiczies found these results “quite logical.” She explained the findings by making a comparison between inflammation in a person’s brain and joints.

“If I have an inflamed joint, for example, an edema forms and it swells up. Once the inflammation subsides, the swelling also goes down,” Waiczies said.

The animals followed a typical relapse-remitting disease progression course, with symptoms developing at day 10, peaking at day 14, and remitting or easing between day 20 and 22.

“Importantly, at the end of the experiment [day 64], while most animals still exhibited a degree of neurological disease severity … VVs had returned to normal baseline values,” the researchers wrote.

The team then evaluated whether the VV enlargement coincided with the breakdown of the blood-brain barrier, a hallmark of the inflammatory process in MS. Of note, this barrier is a highly selective membrane that shields the CNS with its cerebrospinal fluid from the general blood circulation.

For this evaluation, the researchers performed MRI scans using gadolinium-based contrast agents (GBCA) that mark the BBB’s disruption. The results showed gadolinium-enhanced lesions, particularly in several brain regions — specifically the cerebellum and meninges — and around the ventricles by day five. Also, gadolinium enhancement was observed before clinical signs were evident.

Tissue analysis of the animals’ brains showed that the enlargement of the ventricles was followed by an infiltration of inflammatory cells. Moreover, animals with more pronounced VV had the highest inflammation severity.

Next, the researchers assessed whether these dynamic VV changes were also present in MS patients.

MRI scans were analyzed from 33 RRMS patients who participated in a Phase 2 study (NCT00616187) testing the efficacy of the cholesterol-lowering medication atorvastatin. These participants underwent 13 MRI scans during a period of one year.

“I was involved in the immunological planning and evaluation of this study, and I knew that the generated MRI data was extensive and robust,” Waiczies said.

Researchers observed that there was a small yet significant increase of the median VV — of 284 mm3, corresponding to 0.08406% – between the start (baseline) of the trial and the last measurement.

To understand how relevant were the VV changes in MS compared with healthy brains, the team analyzed MRI scans of healthy people taken over a six-month period. They estimated that VV fluctuated by 6%, up or down, in healthy brains.

A large fraction of the MS patients, 21 out 33, or 64%, had changes above the healthy limit of 6%, which occurred within one-month intervals.

Only a small part of the group (five out of 33) had positive fluctuations, with enlargements and no contractions, during the study. In contrast, 24 of 33 (73%) patients showed VV contractions above 6% that were observed over a continuous period of at least two months, without enlargements in between.

Those participants with volume contractions greater than 6% were found to have lower scores in the expanded disability status scale (EDSS) compared with patients without contractions. The EDSS scale is a method of quantifying disability in MS, in which higher scores indicate greater disability.

In addition, patients with contractions also had a significantly shorter disease duration, so they were at earlier disease stages.

“The majority of patients with relapsing-remitting MS exhibited fluctuations in ventricle volume — just as we observed with the mice,” said Jason Millward, PhD, neuroimmunologist at the MDC and Charité and the study’s first author.

The scientists called the results crucial.

Overall, the data show “that VV in RRMS patients does not only increase unidirectionally over time as a result of atrophy, but in the majority of cases, VV expands and contracts dynamically during the disease course,” the researchers wrote.

“We are used to seeing ventricular enlargement in other neurodegenerative diseases — such as Alzheimer’s or Parkinson’s disease. But in those diseases, rather than being reversible, the ventricles just keep expanding,” said Thoralf Niendorf, a study author of the MDC and the Experimental and Clinical Research Center (ECRC), a joint institution of the MDC and Charité.

The team believes that close monitoring of VV changes could constitute a new method to track MS disease activity.

“From a clinical perspective, examining fluctuations in ventricle volumes in routine MRI patient scans could be an interesting approach to monitoring the course of the disease or of immune therapies,” said Friedemann Paul, a clinical neuroimmunologist at Charité and the study’s co-lead author.

“But this will require us to study even larger cohorts over a longer period of time,” Paul added.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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