Rate of Brain Volume Loss Not Adequate as Marker of Treatment Effectiveness in MS Patients, Study Reports

Brain volume loss takes place at a faster rate in the first five years of multiple sclerosis than later in disease course, researchers report in a study that calls for scientists to “reconsider” — for this and related reasons — proposals to use volume loss as a measure of treatment efficacy in MS patients.

The study, “Assessing Biological and Methodological Aspects of Brain Volume Loss in Multiple Sclerosis,” was published in the journal JAMA Neurology.

Achieving no evidence of disease activity (NEDA-3), as defined by three clinical and imaging criteria, has been proposed as an MS treatment goal. But, although a valuable approach to capturing the inflammatory burden of the disease, scientists think that NEDA-3 might underestimate that the extent of nerve fiber injury and its contribution to disability.

Measuring brain volume is one approach being considered as a possible way of marking nerve fiber injury in MS.

Research has shown that brain volume loss (BVL) and brain lesion atrophy correlate positively with physical disability in MS. Results from clinical trials also indicated that disease-modifying therapies reduce the rate of BVL, prompting researchers to suggest expanding NEDA-3 to NEDA-4 by adding a parameter:  a BVL rate of less than 0.4% annually as a therapeutic target.

But to establish BVL as a valid marker, researchers first need to assess specific issues. Namely, they must determine whether BVL is similar throughout the disease course, or if it progresses faster at a given stage. Investigators also need to evaluate if magnetic resonance imaging (MRI) is a suitable way of accurately tracking loss of brain volume, and to confirm its accuracy by attaining similar results using other existing methods to capture changes in brain volume.

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Aiming to address these issues, the research team evaluated brain atrophy throughout the course of MS using two MRI methods – Jacobian Integration (JI) and the Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL), which is a library of imaging analysis tools for MRI. They also compared these two methods in terms of their effectiveness in estimating changes in brain volume.

The study included 140 patients (median age of 40.7) with clinically isolated syndrome or with MS, 95 of which were women. The patients underwent four MRI scans at roughly one-year intervals. Two groups of healthy volunteers — with 34 and 20 participants — underwent two MRI scans.

Results showed that the BVL rate was faster in the immediate five years after MS onset, and was directly associated with the use of steroids but inversely associated with patient age at onset. “Our results suggest that the younger the patient is at MS onset, the faster the rate of gray matter volume loss,” the researchers wrote.

The two MRI techniques were similar when assessing whole-brain volume loss, but JI showed more precise estimates for specific brain regions than did FSL. Data also revealed that the two methods differed in terms of accuracy in discriminating MS patients from healthy volunteers.

Among the study’s limitations, the team mentioned its small sample size, which precluded analysis of different MS types, as well as assessing changes beyond 25 or 30 years of disease duration.

Nonetheless, based on the results, the researchers concluded: “the proposed BVL threshold of less than 0.4% per year as a marker of therapeutic efficiency should be reconsidered because of the different dynamics of BVL as MS progresses and because of the limited reproducibility and variability of estimates using different imaging methods.”