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New findings suggest that thalamic volume should be considered as an MRI metric associated with MS-associated neurodegeneration, a Yale University research team reported.
PHILADELPHIA—Researchers have shown that the thalamus is atrophied in patients with radiologically isolated syndrome (RIS) — often a precursor stage to multiple sclerosis (MS) — and that structural changes to the brain are occurring far earlier than symptoms appear in MS patients.
In a session here at the AAN Annual Meeting, investigators also said they found an area of the cortex, believed to be previously unidentified, that was significantly thinner in RIS patients compared with controls.
The findings suggest that thalamic volume should be considered as an MRI metric associated with neurodegeneration, according to the research team from Yale University.
RIS, which is identified on imaging incidentally, comprises asymptomatic anomalies within the central nervous system that are suggestive of MS. About a third of patients identified as having RIS will go on to have a seminal clinical demyelinating event.
In a 2014 paper in the Journal of Neurological Sciences, another research team reported thalamic atrophy in early demyelinating disease — including earlier relapsing-remitting MS, pediatric MS, and clinically isolated syndrome (CIS).
In this study, researchers set out to investigate the presence of gray matter volume loss and cortical thinning in subjects with RIS. A total of 63 subjects were enrolled, including the controls. Each subject with RIS was assigned two age- and gender-matched healthy controls, said Christina Azevedo, MD, MPH, an assistant professor of neurology in the Advanced Imaging in Multiple Sclerosis Laboratory at the Yale University School of Medicine. [The principle investigator was Daniel Pelletier, MD, professor of neurology and diagnostic radiology; chief of the Division of Neuro-Immunology and the Yale University Multiple Sclerosis Center; and drector of the Advanced Imaging in Multiple Sclerosis Laboratory.]
The researchers were particularly interested in the thalamus, she said, because it is a “major relay center” with widespread cortical and subcortical anatomic connections, and thus might be a location where they could see early signs of MS-associated neurodegeneration.
Researchers did not find any significant differences in the volume of total parenchyma in RIS subjects compared with controls (p=0.12) or in total white matter volume (p=0.56). They started to see a trend, however, in total gray matter volume (p=.06), a difference that turned out to be attributable to variation in subcortical gray matter volume (p=.04). The difference in cortical gray matter volume was not significant.
Examining the thalamus, they found a significant difference in the average total volume (p=0.004), including significant differences in both the right thalamus and left thalamus, compared with controls. But the bigger difference was seen in the right thalamus (p=0.008, compared with 0.006 for the left).
Researchers eventually zeroed in on a 3-cm area in the right superior/inferior parietal gyri, which was significantly thinner in RIS subjects compared with controls.
“We don't have a specific explanation for why it would be these particular gyri, so it deserves further follow up in future studies,” Dr. Azevedo said. She said she believes this area has never been previously identified as a location of interest in RIS patients, and stressed that the finding should be regarded as preliminary.
“These data add to the growing body of evidence that suggests that thalamic atrophy is an early event in CNS demyelinating disease, and that thalamic volume should be considered as an MRI metric that is associated with neurodegeneration,” she said.
“It's likely that thalamic volume loss is the result of more than one aspect of MS-related pathology that's converging,” she explained. “Probably demyelinating lesions within the thalamus contribute to thalamic volume loss. But we also know that in non-lesional thalamic tissue, neuronal density is reduced. And that may be driven by disconnection by white matter lesions in the various areas that are projecting into the thalamus.”
The lab is continuing to look at thalamic atrophy in RIS, with longer longitudinal studies under way. Dr. Azevedo said they hope to define the evolution of thalamic atrophy over time, and would like to identify predictors of thalamic volume loss. They're also interested in looking at thalamic volume in RIS as a predictor of progression in CIS and MS, she said.
Timothy L. Vollmer, MD, FAAN, a professor of neurology at the University of Colorado School of Medicine and co-director of the Rocky Mountain MS Center at Anschutz, said the research into brain atrophy and atrophy of specific gray matter structures now goes back 12 years.
“This study took it one step further,” he said.
Much of the focus in the field is in relapse-rate reduction, but that is “probably the least valuable point of view in thinking about MS,” he said, because brain volume is lost so early, well before clinical symptoms emerge. This study underscores the importance of this, Dr. Vollmer said.
“It re-emphasizes two key points that people keep forgetting when they think about treatment: One is that it's as much a gray matter disease as it is a white matter disease, and it's the gray matter changes that have the higher predictive value for disability.”
Also, he said, “the vast majority of the disease is subclinical and if you're not thinking about that, you miss the point of why you would want to treat early and aggressively.”
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