Research News

Cleveland Clinic researchers have developed a brain imaging method (MRI classifier) that is critical in identifying, investigating and treating progressive MS patients who have a scarcity of the cerebral white matter demyelination widely recognized as a hallmark of the disease in MS research.

MS patients with a paucity of brain white matter demyelination previously could only be identified via brain autopsy. When applied to MRIs from a cohort of 255 living patients, the classifier identified that 22% of patients fit the criteria for a paucity of cerebral white matter demyelination. The findings from the lab of Bruce Trapp, PhD, and published in Acta Neuropathologia, are the first to correlate pathologically confirmed cortical atrophy and neurological disability.

The conventional wisdom in the MS research community was that destruction of the myelin coating around the axons of nerve cells (i.e. demyelination) was the major driver of permanent neurological disability in MS. However, while treatments focusing on demyelination work on patients with relapsing-remitting MS, they have historically not been as effective in treating patients with progressive MS. This has spurred a new research focus for Dr. Trapp over the past 10 years. Dr. Trapp, The Morris R. and Ruth V. Graham Endowed Chair in Biomedical Research and chair of Cleveland Clinic's Department of Neurosciences, further confirmed that neurological disability occurs in progressive MS patients independent of demyelination through his lab’s study of autopsy tissues and identification of living MS patients with a paucity of cerebral white matter demyelination. Clinical studies have identified living MS patients where progression is independent of relapse activity (PIRA) and concluded that cortical atrophy, where the cerebral cortex shrinks, is the best correlate of disability progression in MS.

Dr. Trapp’s lab then collaborated with Kunio Nakamura, PhD and his lab to develop an MRI classifier using data gleaned from autopsy samples that identifies demyelinated lesions in the brains of living MS patients — specifically MS patients with severe neurological disability that feature a small amount of brain demyelination and significant cortical atrophy.  

“Now that we have further solidified that cortical atrophy is the best correlate of neurological disability in progressive MS patients, it is critical to prioritize researching cortical atrophy’s relationship with MS to the same degree that we focused on demyelination over the last 30 years,” says Dr. Trapp, senior author for the study. “We need to pivot as a research community.  A lot of resources will be required, and many different approaches, to figure out why exactly the MS brain shrinks as it does.”

The ability to determine demyelinated lesion volume and cortical atrophy provides a more nuanced read of MS brain pathology in real time and will in turn result in improved monitoring of treatment response in patients.  

MRI classifier, new data enable future of MS research

Developing a reliable imaging method enables investigating cortical atrophy’s role in driving disability in progressive MS and better understanding its disease mechanisms – work that the lab has already commenced. The MRI classifier allows researchers to detect a scarcity of demyelination in living patients, ensuring more accurate and effective patient inclusion in clinical trials.

“Our research shows that a significant number of people with MS may have less white matter demyelination than previously thought. Instead, these patients’ symptoms may be caused by different mechanisms, including injury to the cortical gray matter and spinal cord,” explains Daniel Ontaneda, MD, PhD, Clinical Director of the brain donation program at Cleveland Clinic and Director of Research at the Mellen Center for Treatment and Research in MS and co-author of the study. “Our findings have critical implications both for clinical trials, especially those focused on remyelination of white matter lesions, and more generally for how people with MS accumulate disability.”

Dr. Ontaneda says more accurate inclusion in clinical trials will improve the outcome measures for potential treatments. Dr. Trapp is hopeful a potential treatment could target whatever is causing the cortical atrophy in the first place, and then be used in combination with existing medications that are primarily prescribed for MS relapses.

“We’re talking about transforming a fundamental aspect of MS pathogenesis that has dominated MS research for decades,” he says. “But now that we and others have pinpointed the vital focus area of cortical atrophy, that’s a significant hurdle cleared. I’m hopeful as researchers we can collectively shift our focus and delve into studying cortical atrophy’s relationship to MS.”