Researchers have identified a new subtype of multiple sclerosis (MS), one marked by nerve cell degeneration that occurs independently of immune system attacks against myelin, a process known as demyelination and considered a hallmark of MS.
The new subtype — called myelocortical MS — is indistinguishable from others in the MS spectrum using conventional magnetic resonance imaging (MRI), highlighting the need for more sensitive MRI imaging techniques.
This finding unmasks a previously unknown heterogeneity within MS, and may make possible more personalized therapies for patients.
“This study opens up a new arena in MS research. It is the first to provide pathological evidence that neuronal degeneration can occur without white matter myelin loss in the brains of patients with the disease,” Bruce Trapp, PhD, chair of the Cleveland Clinic’s Lerner Research Institute Department of Neurosciences and the study’s lead author, said in a press release.
“This information highlights the need for combination therapies to stop disability progression in MS,” Trapp added.
The study, “Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study,” was published in The Lancet Neurology journal.
White matter makes up half the human brain and is the prime target for the immune system attacks in MS. It contains nerve fibers (axons) — the long extensions of neurons — which are surrounded by a protective coat of myelin, the insulating substance that works to speed signals, or communication, between nerve cells. This coating is the particular target of attacks by certain immune system cells in a process known as demyelination.
In myelocortical MS, the newly discovered subtype, nerve cells die but there is no evidence of demyelination in the brain’s white matter.
In their study, Cleveland Clinic researchers looked at brain tissue samples from 100 MS patients who had donated their brains upon death. In 12 of these patients, they found no traces of white matter demyelination.
They then did a deeper analysis, comparing brain tissue from these 12 patients with 12 tissue samples from those known to have MS, and with brain samples from individuals free of any neurological disease.
The team found MS demyelinated lesions in the spinal cord and cerebral cortex — the cerebrum’s outer layer, a gray matter part of the brain responsible for memory and information processing — in both myelocortical and typical MS patient samples. But demyelinated lesions affecting the brain’s white matter were detected in MS patients only.
Brains of patients with myelocortical MS nonetheless showed signs of degeneration, detected by a lower number of neurons and a reduction in the brain’s thickness, a feature also known to MS. For instance, brains from healthy controls showed a mean neuronal density of 419 nerve cells per square millimeter (mm2) in layer 3 of the cerebral cortex (a layer that receives input from other cortical areas), while those with myelocortical MS had 349.8 neurons per mm2 in this layer, a significant decrease. Similar and significant decreases in cortical nerve cell densities between these two groups were also seen in other cerebral cortex layers.
Altogether, these results show that, contrary to what was previously believed, the death of neurons in MS can occur without signs of white matter demyelination.
“We propose that myelocortical multiple sclerosis is a subtype of multiple sclerosis that is characterised by demyelination of spinal cord and cerebral cortex but not of cerebral white matter,” the researchers wrote, adding that the “identification of a new subtype of multiple sclerosis supports the concept that multiple sclerosis is a complex disease with multiple underlying disease mechanisms.”
Daniel Ontaneda, MD, clinical director of the brain donation program at Cleveland Clinic’s Mellen Center for MS and a study author, added: “The importance of this research is two-fold. The identification of this new MS subtype highlights the need to develop more sensitive strategies for properly diagnosing and understanding the pathology of MCMS [myelocortical MS]. We are hopeful these findings will lead to new tailored treatment strategies for patients living with different forms of MS.”
The team emphasized that identifying signs of myelocortical MS in patients will require “sensitive brain imaging modalities that reliably delineate myelinated and demyelinated cerebral white matter.”
The study was supported by the National Multiple Sclerosis Society and the National Institute of Neurological Disorders and Stroke.