In 2018, investigators confirmed that one of the staple symptoms of multiple sclerosis—white matter demyelination—isn't always consistent.
Bruce Trapp, PhD, collected the first brain in May 1998. The Department Chair of Neurosciences at the Cleveland Clinic was analyzing the brains and spinal cords of former multiple sclerosis (MS) patient donors with his team, assessing the characteristics that define the neurodegenerative disease.
What’s needed to be known of MS in order to adequately spot it, treat it, and limit its dimensional damage to patients’ inflammatory and neurological systems is still being sought, and what’s already known requires more scrutiny for confirmation. Trapp and his team affirmed the significance of the latter task with a patient’s brain they received 20 years ago.
The Cleveland Clinic investigators uncovered a brain—and 11 more like it—which carried no distinctive lesions, the marker which clinicians use to indicate white matter demyelination in patients with MS. These dozen brains, among 100 analyzed by Trapp’s team through 2012, lacked a distinctive marker of MS, despite coming from patients with an obvious MS diagnosis.
Trapp, in collaboration with the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, had identified the first known patients of a new MS subtype: myelocortical MS (MCMS). But their first reaction was to challenge the patients’ initial MS diagnosis, Daniel Ontaneda, MD, MSc, of the Mellen Center, told MD Magazine®.
“Bruce went back to us and asked if we had misdiagnosed,” Ontaneda recalled. “After our first couple of new cases, it was proven to be typical MS. That’s when it piqued our interest to look at it in a more systematic fashion.”In a study published in The Lancet Neurology this August, Trapp and colleagues explained how the 12 brain tissue samples identified as having been inflicted with MCMS showed signs of spinal cord demyelination and cortical lesions, but no white matter demyelination.
The indication led to the challenge of a fundamental understanding in MS pathology: If white matter demyelination causes patients’ neurodegeneration, typical MS patients should be experiencing greater neuronal loss than those with MCMS, Trapp said in an interview with MD Mag sister publication NeurologyLive. But that wasn’t the case.
“Compared to control brains, there was more neuronal loss in myelocortical MS,” Trapp explained. “We looked at 5 cortical regions and looked at 3 layers in these 5 regions—these are the layers that project axons to the white matter projection neurons—and in myelocortical MS, 11 of 15 of those layers had decreased densities compared to control, whereas in typical MS only 5 out of the 15 had a decrease.”
Trapp noted this discovery of disassociation between MS and demyelination is not a new one: the imaging and MRI communities, he explained, had previously presented data supporting that brain atrophy precedes most demyelination as measured by MRI.
“So, the concept isn’t novel, but to date there has been no pathological evidence that provides support for that,” Trapp said. “The myelocortical MS gave us a very nice platform for studying that.”
Ontaneda explained this has several implications surrounding the heterogeneity of the disease. It’s not uncommon for patients to display benign lesion rates on MRIs then suffer from severe MS progression, or to display severe lesions then remain clinically well. This is indicative of the clinical difficulty in predicting MS progression—a difficulty compounded by the fact that the brain tissue of patients with MCMS reported lesions in similar sizes and regions to that of their typical MS counterparts.
The discovery throws a wrench in the notion that demyelination drives the entirety of MS symptoms, if only by proving it is not associated with cortex neurodegeneration, Ontaneda noted. “Whatever’s going on, if it’s not the myelin causing that, it’s something else,” he said.
Ontaneda has his first theories fixed on the axon: the greatest commonality shown among patients with MCMS was swollen axons, indicating that differences in white matter demyelination may be due to axon swelling increasing free water in the brain. He foresees the research teams investing a great portion of their to observing axon pathology and characteristics.
The benefits of uncovering those answers may be exponential: new biomarkers, which improve diagnoses, which improve the potential for therapy success.
“The only current way we can identify MCMS patients is under a microscope,” Ontaneda said. “I think as a tool, the presence of MCMS lends to leveraged research looking at more refined MRI assessments, which would be more helpful in setting specificity for clinical trials and diagnosis.”
The booming potential for MS biomarker discovery due to the neurofilament indication of neurodegeneration gives Trapp hope such findings are possible through further MCMS research.
“That technology is going to advance and hopefully, the list of molecules in those types of platforms will increase and it’ll be possible that one could help distinguish myelocortical MS from typical MS,” he told NeuroLive.Even therapeutics in MS could stand to benefit from the implications of the MCMS discovery. Ontaneda observed that the rate of slightly less inflammation observed in patients with myelocortical MS could indicate they would respond differently to anti-inflammatory drugs.
It could also affect how potential therapies are observed in clinical trials. He noted that it’s become common practice for trials to depend on MRI measures of patients’ white matter. Additionally, many new MS therapies are defined by their remyelinating characteristics.
“So, we give a patient a punitive medication that will form myelin again, and we’re measuring lesions in the brain to see if their myelin content has increased in the MRI,” Ontaneda explained. “We think it has implications for treatment, specifically for remyelinating therapies.”
After 2 decades of research, the team may have more questions than answers. But at least, it’s questions that could lead to greater progress in treating a disease in need of better answers. Ontaneda looked at the MCMS subtype discovery as a good, clean contrast, by which he and colleagues can take the right paths to finding key biomarkers and the underpinning of MS.
“I think the discovery is important not only for having identified a subtype, but the biological difference of the subtype will allow us to really understand a little bit more about why the disease actually occurs and how the damage incurs,” he said.
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