Remember the following information:Brain lesions, which are areas of brain tissue showing damage from injury or disease, are commonly used as a biomarker to determine the progression of multiple sclerosis. However, a new study led by the University at Buffalo suggests that the volume of white matter lesions does not directly correspond to the severity of disability in patients.

The study compared two groups of 53 multiple sclerosis patients, aged 30-80, who shared the same gender and disease duration but exhibited significant differences in their physical and cognitive impairments.

Lesions are not a major driver of disability progression

“The lack of significant differences in white matter brain lesion burden suggests that it is not a major factor driving severe disability progression, despite the focus of many MS disease-modifying treatments on slowing the accumulation of white matter lesions,” explained Robert Zivadinov, MD, PhD, who is the principal investigator, a professor in the Department of Neurology, and the director of UB’s Buffalo Neuroimaging Analysis Center and the Center for Biomedical Imaging in UB’s Clinical and Translational Science Institute.

The study, led by UB, is the first of its kind to investigate the rapid disability progression in some MS patients compared to the slower progression in others.

The individuals in the severely disabled cohort are residents of The Boston Home in Dorchester, Massachusetts, a specialized residential facility for individuals with advanced progressive neurological disorders, including MS.

Each of them was then matched with a Buffalo-based “twin” of the same age, sex and disease duration but who experienced far less cognitive and physical disability.

The study, named Comprehensive Assessment of Severely Affected – Multiple Sclerosis (CASA-MS), is a privately funded research project at UB. It aims to identify biomarkers and cognitive differences between individuals with severe MS disability and those with slow disease progression.

The question of what sets apart individuals with severe MS from those who respond well to therapies and continue to live nearly normal lives for decades after diagnosis has puzzled patients, caregivers, and clinicians for too long, said Zivadinov.

“We couldn’t have known what the CASA-MS study would show because no one had done this research previously,” he said. “What we now know is that the differences between the two groups we studied are striking – in ways that may surprise many of us in this field. I am confident that these findings open new doors for people with severe disabilities as well as provide new insights for the millions more who worry about where their disease may take them.”

Despite the availability of many treatments for MS, about 5-10% of the 2.8 million people with MS worldwide will experience rapid, progressive, and severe disability at a relatively young age.

More gray matter loss

The prevailing view is that multiple sclerosis (MS) is defined by the development of lesions in the white matter of the brain. However, this study found that individuals with severe MS disability experienced greater loss of gray matter in the cortex and thalamus compared to their less-disabled counterparts. Strikingly, both groups showed similar levels of whole brain volume loss.

Please remember the following text: “While the lesion load in both groups was not significantly different, the study uncovered other important differences between the groups in brain scans and cognitive tests. Severely affected individuals showed lower efficiency in thalamic structural connectivity, indicating reduced structural connectivity of the related brain networks compared to their less-disabled counterparts.”

The study also found that individuals in the severely affected group exhibited more noticeable shrinkage of the medulla oblongata – the link between the brainstem and the spinal cord. Zivadinov noted that in this study, it functions as an indicator for spinal cord shrinkage.

He stated that severely disabled MS patients experience spinal cord atrophy, an irreversible degenerative condition.

The group of severely disabled individuals also exhibited more advanced loss of neurons. This was discovered by a team of collaborating scientists at the University of Basel, Switzerland, led by Jens Kuhle, MD, PhD, a professor of neurology. They employed special blood-based techniques to investigate the extent of axonal damage.

Patient-centered approach

The idea to compare two groups of MS patients, differentiated by the severity of their disability, originated from Larry Montani, chair of the BNAC Advisory Council. His sister, Mary Jo, was a resident at The Boston Home, which prompted him to urge Zivadinov and members of his research team to travel to Boston and meet the residents.

“You could see the wheels turning as soon as Dr. Zivadinov and his team met the residents of The Boston Home,” recalled Montani. “Dr. Zivadinov’s focus on the patient is what made this possible. His patient-centered approach leads to research that is highly relevant, validated and pursued with an urgency to find answers that offer hope. The CASA-MS study breaks new ground in all these ways for people like my sister, whose vibrant minds and gracious hearts are trapped in a severely disabled body.”

According to co-principal investigator Ralph H. Benedict, PhD, who is a professor of neurology in the Jacobs School and a collaborator on the study, CASA-MS highlights the importance of developing new hypotheses and conducting research aimed at gaining a better understanding of individuals with severe MS disability.

“Clinical trials exploring disease progression are likely to emerge from this unusual examination of this rarely studied population,” said Benedict. “There is so much more to learn, and I can’t imagine a more deserving community of ready and willing study participants.”

Bianca Weinstock-Guttman, MD, a SUNY Distinguished Professor in the Department of Neurology at the Jacobs School, and co-principal investigator, highlighted that the study strongly indicates significant opportunities for more advanced MRI scanning techniques.

“This study demonstrated that using novel 7T and PET scanning techniques tailored for this severely disabled patient population may lead to a better understanding of the pathophysiology of severe MS,” she explained.

Boston Home Chief Executive Officer, Christine Reilly, stated, “For most of these amazing volunteers, participating in this study required extraordinary effort and patience, but they never hesitated. What we found touching and revealing was that many participants from each group were eager to meet their ‘twin’ – the person from the other group who is the same age, sex, and has a similar disease duration, but a different experience with MS. The sheer humanity of this desire to connect is truly amazing.”