A team of investigators report that damage to the cortex (the outer part of the brain) occurred in brain tissue samples from 43% of people who went on to develop MS. Damage to the cortex has been associated with disease progression and cognitive impairment. The team also reported observing some nerve cell and nerve fiber damage, but this was associated with immune system activity, and did not appear to be occurring independently. Understanding the sequence and timing of nervous system-damaging events in MS should offer new opportunities for blocking this damage to stop MS disease progression. Claudia F. Lucchinetti, MD (Mayo Clinic and Foundation), Richard M. Ransohoff, MD (Cleveland Clinic Foundation) and colleagues report these findings in The New England Journal of Medicine (2011;365:2188-97).
The team was funded in part by the National MS Society’s MS Lesion Project (link to Targeted Research-Lesion Project)– funded through targeted research campaigns including the Promise:2010 campaign. Exploring patterns of disease activity in brain tissue samples was the focus of this path-breaking international collaboration. Dr. Lucchinetti and collaborators from the U.S., Germany and Austria amassed a large collection of tissue samples from people with MS – a painstaking effort, because these are obtained through brain biopsies (a rare procedure) or autopsy. The team then leveraged Society funding, earning a grant from the National Institutes of Health (NIH) to use their database to study damage to the cortex in MS and how this damage may specifically impact MS. The NIH grant funds this paper as well.
Background: MS occurs when the immune system attacks the brain and spinal cord. A primary target of the attack is the myelin that surrounds nerve fibers. Nerve cells and fibers are damaged as well, and it is not clear if this damage results from the immune attack or occurs separately from the attack.
Recent advances have made it clear that MS lesions, which are focal points of disease activity, are not limited to the “white matter” of the brain as once thought, but they also occur in the “gray matter” including the cortex, an area of the brain where nerve cell bodies are lodged which is associated with higher brain functions. Gray matter lesions are not easily detected with standard MRI scans.
The Study: Investigators collected brain tissue samples from 138 people who had undergone biopsies for other issues, such as suspected brain tumors. The team looked at the presence of myelin damage in the cortex, and whether damage in the cortex was associated with immune system activity and damage to nerve cells; clinical outcomes were also looked at in a subgroup of 77 patients who had been followed for several years.
In this subgroup, 58 people went on to develop definite MS, and 43% of the group with MS had signs of myelin damage in the cortex. Damage to the cortex was associated with specific immune T cell activity, and – in a small subgroup of people with MS – with inflammation in the meninges, the membrane that encloses the brain. Some nerve cell and nerve fiber damage was observed, but this was associated with immune system activity, and did not appear to be occurring independently in this study. The authors speculate that immune system activity in the meninges may re-stimulate the immune attack, contributing to disease progression.
Comment: This study sheds more light on the underlying disease activity that may occur in people in the earliest stages of MS. Collaborative initiatives such as the MS Lesion Project –which move forward our understanding of the sequence and timing of nervous system-damaging events in MS – should offer new opportunities for blocking this damage to stop MS disease progression. As the authors note in their paper, further study is needed to determine the association between tissue damage in the cortex, cognitive function, and MS progression.