Gray Matter Pathology in MS: Key Research Advances

Although multiple sclerosis (MS) has long been known to affect white matter in the central nervous system (CNS), more recent research has established that MS extensively impacts cortical and deep grey matter as well.

At the American Neurological Association’s 145th Annual Meeting, Caterina Mainero, MD, PhD, gave a talk on gray matter pathology in MS. After Dr Mainero’s presentation, Neurology Learning Network caught up with her about important research advances in this area.

Dr Mainero is an associate professor of Radiology at Harvard Medical School, assistant in neuroscience at Massachusetts General Hospital, and director of Multiple Sclerosis Research at the Athinoula Martinos Center for Biomedical Imaging in Massachusetts.

Neurology Learning Network: What have been some important recent research developments regarding gray matter pathology in multiple sclerosis?

Dr Mainero: We know that the involvement of gray matter is an established component of MS pathology, and detailed neuropathologic examination has revealed that gray matter is extensively involved across the central nervous system (CNS), spanning from the deep gray matter, especially the thalamus, the cortex, the spinal cord, and the cerebellum. We know also that the greatest mark of gray matter pathology is constituted by cortical demyelinating lesions. Cortical demyelination has been overlooked for a long time in MS due to the lack of sensitive imaging methods in the clinic. Most of the information we have on cortical lesions derives from histopathological examination on the brains of patients with MS, which are usually performed on postmortem tissue of late-stage disease.

Nevertheless, in recent years, there has been some improvement in magnetic resonance imaging (MRI) technology with the implementation of imaging protocols in clinic that better allow us to see cortical lesions among patients and also with the use of ultra high field (7 Tesla) MRI scanners, which have been recently cleared by the FDA for clinical studies. Studies using these novel technologies have shown that cortical lesions can develop from the earlier stages of MS, that they accumulate over time, and that they relate to disease progression, neurological disability, and reduced cognitive performance. This is independent of white matter lesions, which traditionally are considered the pathological hallmark.

Another finding, which has emerged from neuropathological examination, is the observation that a certain type of cortical lesion— the subpial lesions that involve the outer layers of the cortex—can only be seen in MS. They are not observed in other conditions that may mimic MS.

Based on all of these findings, cortical lesions have actually been included recently in the diagnostic criteria of the disease and can also be very important for the differential diagnosis. I think most of the important research and developments have focused on the study of the cortex, from neuropathological perspective as well as the imaging perspective.

NLN: What areas of future research are still needed in this field?

Dr Mainero: There are areas of research that are still open regarding gray matter pathology and cortical pathology—first, how it relates to white matter pathology, which has been better characterized and best known in MS. This research is to improve the technology that we have for detecting cortical lesions. Despite the novel implementations in MRI, even these improvements cannot allow us to see the entire cortical lesion burden among patients. We know for neuropathology that a large portion of these lesions can still be missed, even if we're using ultra-high field MRI. There need to be further improvements with these MRI technologies.

From a pathological perspective, we do not know how gray matter pathology develops or what triggers it. Specifically, I am referring to inflammation, which is a relevant component in the development of white matter lesions that are the traditional hallmark of MS disease. We still don't know the role of inflammation in gray matter lesion pathogenesis and cortical lesion pathogenesis because there have been conflicting findings from neuropathology. The first descriptions of cortical lesions reported these lesions to be less inflammatory than white matter lesions, to have no brain-barrier disturbance, and to have no perivascular infiltrates. However, there have been subsequent neuropathological studies that have shown extensive inflammation in the meninges of MS brain topographically associated with areas of cortical demyelination.

Sometimes, this inflammation organizes in follicles, lymphoid‑like structures that are very small, like on the order of 100-μm dimension. They're very hard to image in vivo, so we don't have the technology to see these structures in vivo. There have been some attempts to look at meningeal inflammation among patients—for example, using fluid-attenuated inversion recovery (FLAIR) sequences that are conventional protocols that we acquire with MRI in clinic after the administration of gadolinium, which is a contrast agent.

Neurologists and radiologists look at these images and have noticed some areas that light up, some areas of leptomeningeal inflammation. In some cases, there has been a verification that these areas actually localize with pathological areas of meningeal inflammation. This radiological sign, which is called the leptomeningeal enhancement sign, can be seen also in diseases other than MS, as well as other inflammatory brain conditions, so it is not specific to MS. It seems to be an indirect sign of inflammation that is caused by fibrotic tissue pockets that trap the contrast agent. These fibrotic pockets in the meninges are thought to form after repetitive episodes of inflammation. These areas of leptomeningeal enhancement are very few in patients, so they do not resemble the extensive inflammation that has been described by neuropathological examinations, for example. They also tend to be fixed in time and space. There have been a few studies that have shown that they are not modified by treatment.

Also, research has yet to reveal the relation with cortical lesions, as some investigators have reported that there is an association between the presence of this radiological sign and the lesions in the cortex, while others have not. Still, we need to improve our methods of assessing inflammation so we can shed more light on its role in gray matter lesion pathogenesis.

NLN: What key takeaways about gray matter pathology in MS do you hope to leave with neurologists and neurology providers?

Dr Mainero: I think it is established now that gray matter is extensively involved in the course of the disease. It is really difficult to image some aspects of gray matter pathology in vivo, but we have some tools now that allow us to see, if not the whole burden of gray matter lesions, at least some of these lesions. I would advise clinicians to try to add these protocols to their clinical routines because they can be helpful, for example, for differential diagnosis. It also helps us see how the disease evolves over time and gives a more complete picture of the disease among patients with MS. This technology has been implemented, but of course, we need to standardize protocols across centers so we can conduct larger studies. We will likely have more answers in the future once these steps are achieved.

—Christina Vogt

Mainero C. Gray matter pathology. Talk presented at: ECTRIMS/ACTRIMS MSVirtual2020. September 13, 2020.