Gray Matter Imaging Reveals MS Changes Missed on Standard MRI

Nancy A. Melville

May 31, 2019

UPDATED June 3, 2019 // SEATTLE — Automated three-dimensional (3D) MRI volumetric measurement of gray matter structures in the brain in patients with primary progressive multiple sclerosis (PPMS) reveals significant volume loss and other abnormalities that typically would not be detected on standard MRI of white matter for patients with MS, offering potentially essential insights for clinical decision making, a new study suggests.

Although use of conventional MRI for patients with MS focuses largely on lesions found in the white matter of the brain, the technology is less sensitive to gray matter structures, owing to the lower contrast of these structures.

Important changes in gray matter structures, including the hippocampus, the amygdala, and the thalamus, are known to occur in patients with PPMS, particularly in relation to cognitive decline. Such changes often go undetected.

"One of the major limitations of a standard MRI is that one doesn't see the lesions or the changes that take place in gray matter until very late in the disease," lead author Ted Rothstein, MD, of the Department of Neurology, George Washington University, Washington, DC, told Medscape Medical News.

"Meanwhile, there is a tendency for physicians and neurologists to assume that standard MRI is sufficient in evaluating whether there are new lesions or if DMTs [disease-modifying therapies] are working when in fact there are new imaging technologies that really advance our understanding of what's happening," he said.

Rothstein described results for 10 randomly selected patients with PPMS who underwent gray matter imaging performed with an automated 3D MRI brain volume measurement software program (NeuroQuant, CoreTechs Labs, San Diego, California).

The patients each underwent at least two MRIs of the brain. Voxel-based measures were taken of the whole brain, the cortical gray matter, the forebrain, the parenchyma, the hippocampus, the thalamus, and the superior and inferior lateral ventricles.

Imaging of gray matter structures showed that for 7 of the 10 patients, whole-brain volumes were below the fifth percentile for the patient's age, compared to normative data.

Other gray matter structures in which volumes were in the less than the fifth percentile for the patient's age were the cortical gray matter (10 patients), the forebrain parenchyma (8), the thalamus (8), and the hippocampus (5).

In addition, superior lateral ventricles and inferior lateral ventricles were either at or greater than the 95th percentile in nine and seven patients, respectively, which is beyond the range of normal.

Rothstein noted that enlargement of the superior lateral ventricle reflects a loss of whole-brain volume, while the inferior lateral ventricle surrounds the hippocampus and enlarges as the volume of hippocampus tissue declines.

"The rate of brain atrophy in the majority of our patients far exceeded the reported findings of 0.5% to 1.49% annually for PPMS," Rothstein reported.

For example, one of the patients showed a 20.61% loss of hippocampal volume in 38 months, he said.

The findings "reveal unprecedented increases in the rate of tissue damage loss in cerebral cortex and deep gray matter nuclei experienced by most of our PPMS patients over time," Rothstein said.

Clinico-Radiological Paradox

Importantly, in the study, the patients' clinical and cognitive disability measures correlated more strongly with the tissue loss observed in the cerebral cortex and the deep gray matter nuclei than with the patients' white matter lesion load.

Rothstein underscored that such findings are consistent with the concept of the "clinico-radiological paradox," notably described in an article by Dutch neuroradiologist Frederik Barkhof, MD, published in 2002.

"With the clinico-radiological paradox, what is seen in standard MRI seems to be disproportionate to what a patient has clinically," Rothstein explained.

For example, a patient with MS may have an exacerbation for which no evidence is seen in the white matter or the spinal cord on standard MRI because the lesion is likely in the gray matter, Rothstein said.

"Patients can have a paucity of lesions in the white matter but have devastating clinical consequences, because the lesions are in the gray matter, yet they're not being seen with conventional MRI," he said.

Likewise, patients may have numerous lesions in the white matter yet not have many symptoms because they may not have much involvement in the gray matter, Rothstein added.

The ability to detect and track such gray matter changes over time could have critical clinical implications, Rothstein explained.

"Let's say the patient is being treated with [the MS disease-modifying therapy] fingolimod, for instance, and has no new visual or motor complaints, but they do have cognitive complaints. As is common, despite these symptoms, the patient may have no new lesions, and their EDSS hasn't changed because they're not walking with a cane," he said.

"Yet, you do this gray matter testing and you see the gray matter volumes are changing from, for instance, the 70th percentile to the 30th percentile over a short period of time. This patient is no longer in a status of 'no evidence of disease activity,' which is a clinician's criterion for keeping the patient on a given medicine.

"So this gives you important, objective evidence that they are losing gray matter and the medicine you're using is clearly not protective, and they may need something more potent."

Imaging in Determining Drug Efficacy

Rothstein argued that such testing should be used in assessing the efficacy of therapeutic agents.

"None of the drug manufacturers thus far have been using gray matter volumes to analyze the efficacy of their therapeutic agents during clinical trials, and as a consequence, you're only getting partial information," he said.

"If the idea of treatment is evidence for no new disease activity, [the assessment] should not only be whether there are new lesions on the white matter but whether the patient is experiencing loss in gray matter volumes in the critical structures that are important for cognition," Rothstein said.

Clinical drug trials commonly consider EDSS, relapse rate, and white matter plaque burden, but that system likewise falls short in alerting physicians to subjective symptoms that are important in tracking disease progression.

"A patient could have severe fatigue and cognitive decline which makes it difficult for them to even work or communicate, yet it's only when they're walking with a cane that the EDSS score goes up significantly," he noted.

Importantly, Rothstein noted that at his center, the inclusion of gray matter imaging adds only about 7 minutes to the time the patient spends in the MRI scanner, at an additional cost of about $80.

"So this is a relatively low-cost but significant contribution to our understanding of what is really taking place with our patients," he said.

"It's not a huge imposition either on insurance companies or on patients to do the [gray matter] assessment," he said.

Rothstein said the software used for the volumetric measurement of gray matter has been used at George Washington University's Department of Neurology since 2011. Although the NeuroQuant software was used for the study, a variety of similar programs are available to neurologists.

The technology is already approved by the US Food and Drug Administration for the assessment of gray matter to track cognitive decline in patients with Alzheimer's disease.

"We know that cognitive impairment occurs in 70% to 80% of patients with MS, so it seems obvious to suggest why not use this with them?" Rothstein said.

Commonly Overlooked

Daniel S. Reich, MD, PhD, chief of the Translational Neuroradiology Section at the National Institute of Neurological Disorders and Stroke (NINDS), in Bethesda, Maryland, agreed that gray matter is indeed commonly overlooked, owing to the limitations of conventional imaging.

"It's a lot harder to see," he told Medscape Medical News. "People tend not to look at it, and it's routinely ignored, yet we know from studies that it's one of the major pieces of the puzzle in progression."

He noted, however, that it doesn't necessarily explain the whole picture.

"Just like white matter, gray matter doesn't tell the whole picture," Reich said. "It's pretty clear there are many different processes evolving at different rates in different people that are together generating the clinical picture that we see, and it's extremely difficult to build a good model, so you get this paradox."

Reich noted that his laboratory is involved in intensive effort to develop new methods for directly seeing the effect of MS on the gray matter, "not just in terms of how it's shrinking but also in terms of other factors, including the loss of myelin and cells, as well as inflammation in gray matter, which has been extremely difficult to do for technical reasons," he said.

Although various specialized techniques can image those factors, Reich is hoping the powerful 7 Tesla MRI will give a fuller picture.

"It has been extremely difficult to see those things on imaging. However, this is one of the areas where I think 7 Tesla will make a difference in terms of directly seeing the damage [associated with MS]. Once we see that, we can ask what the consequences over time once it appears," he said.

Last year, Reich and his team reported that they were able to double the sensitivity in imaging cortical plaques.

"We still don't see as well as we'd like to, but I think we are prying open the door a little more," he said.

Rothstein has disclosed no relevant financial relationships. Reich's work is funded by the NINDS Intramural Research Program. His laboratory is supported by the Adelson Medical Research Foundation.

Consortium of Multiple Sclerosis Centers (CMSC) 2019 Annual Meeting (CMSC): Abstract IMG06. Presented May 30, 2019.

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