Disability Can Be Independent of Cerebral White Matter Demyelination in Progressive MS

New research from Cleveland Clinic is challenging long-held assumptions about the pathogenic mechanisms behind disability in progressive multiple sclerosis (MS). The findings suggest that permanent neurological disability can develop independent of cerebral white matter demyelination in a considerable subset of patients.

The research, led by the lab of Bruce Trapp, PhD, and published in Acta Neuropathologica (2024;148:34), involved development and validation of an MRI classifier that successfully identified myelocortical MS (MCMS), a variant characterized by minimal cerebral white matter demyelination despite significant disability. When applied to living patients with progressive MS, the classifier revealed that 22% demonstrated disability progression with minimal cerebral white matter demyelination. The findings are the first to correlate pathologically confirmed cortical atrophy and neurological disability.

Study rationale and design

The investigation stemmed from previous observations that immune-modulating therapies, while effective at reducing gadolinium-enhanced lesions and clinical relapses, show limited impact on disability progression. Additionally, earlier research by Dr. Trapp’s group and others had identified that T2 lesion volume explains less than 30% of brain atrophy variance and found that 45% of T2-weighted lesions in secondary progressive MS postmortem brains remain myelinated. Compared with aged-matched control brains, cortical neuronal loss was similar in cases with and without cerebral white matter demyelination.

The study employed a multiphase approach:

• Initial investigation of postmortem tissue from previously characterized MCMS (n = 10) and typical MS cases (n = 12)
• Development of an MRI classifier using T1 intensity thresholds to distinguish between myelinated and demyelinated white matter lesions
• Validation of the classifier in 36 uncharacterized postmortem brains
• Application of the classifier to baseline MRIs from 255 living patients with progressive MS who participated in the SPRINT-MS clinical trial

Development of the MRI classifier was a collaboration between the labs of Dr. Trapp and brain imaging research scientist Kunio Nakamura, PhD, both in Cleveland Clinic Lerner Research Institute.

Key findings

The researchers made several significant discoveries:

• Distribution pattern. Myelinated T2 hyperintensities in MCMS showed a distinctive contiguous periventricular distribution, with expansion at the occipital poles of the lateral ventricles. This region demonstrated a surface-in gradient of myelinated axonal degeneration.
• Classifier accuracy. The MRI classifier distinguished pathologically confirmed postmortem MCMS and typical MS cases with 94% accuracy. When applied to SPRINT-MS participants, it identified 78% as typical MS, 10% as MCMS, and 12% with minimal cerebral T1 and T2 intensities. In view of the combined size of the latter two groups, the investigators write: “A paucity of cerebral white matter demyelination in 22% of living progressive MS patients raises questions regarding a primary role for cerebral white matter demyelination in disability progression in all MS patients.”
• Disability metrics. Notably, among SPRINT-MS patients, MCMS patients showed similar Expanded Disability Status Scale scores and brain atrophy measures compared with typical MS patients, despite minimal cerebral white matter demyelination.

Implications

The researchers note that their findings have substantial implications for both clinical practice and research:

• Treatment trials. The identification of MCMS patients (22% of the study population) raises important considerations for clinical trial design, particularly in remyelination studies. Including MCMS patients in such trials could potentially mask treatment effects.
• Pathogenic mechanisms. The study provides strong evidence for disability progression independent of cerebral white matter demyelination, supporting the concept that MS involves an insidious neurodegenerative process characterized by widespread cortical atrophy.
• Surface-in gradient. The identification of a surface-in gradient of neurodegeneration at multiple sites (pial surface, third ventricle, lateral ventricle) suggests a possible CSF-associated mechanism requiring further investigation.

“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 past 30 years,” says Dr. Trapp, the study’s senior author and Chair of the Department of Neurosciences. “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.”

“Our research shows that a significant number of people with MS may have less white matter demyelination than previously thought,” adds co-author Daniel Ontaneda, MD, PhD, Director of Research for Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research. “Instead, these patients’ symptoms may be caused by different mechanisms, including injury to the cortical gray matter and spinal cord. Our findings have critical implications 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 of disease types 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 primarily prescribed for relapsing MS.

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