From the Drawing Board to the Clinic
By Dan Harvey
Radiology Today
Vol. 20 No. 9 P. 14

High-field MRI reveals valuable insights about MS.

For a long time, multiple sclerosis (MS) has confounded physicians. The disease, which impacts the nervous system, varies in terms of symptoms and severity level. One patient may present with no overtly profound symptoms; others may suffer significant physical disability.

Whatever the case, physicians have responded by providing treatment regimens that can involve prescribed medication, dietary alterations, recommendations about programmatic exercise, approaches to lifestyle change, and even alternative therapeutic regulation.

Meanwhile, something has remained elusive, and it has to do with root-cause analysis and the necessary quantification: Is it possible to accurately come up with a quantifying picture of MS progression and uncover why the condition demonstrates problematic variability?

Much is already known. The disease involves a bodily malfunction, wherein the immune system—a protective mechanism—begins attacking myelin, the coating that protects nerves. Myelin is formed in the central nervous system and the peripheral nervous system. It serves as an insulator, protecting nerve axons. Such insulation facilitates rapid transfer of information from one nerve cell to another. MS creates a situation similar to an electrical wire without protective plastic coating.

Now, computer technology applied to imaging technology offers new ways to deploy MR-acquired data. This helps with central nervous system cartography and indicates a new medical direction. In the past two decades, several significant neuropathological studies—using novel staining for myelin—demonstrated that the cortex is frequently the site of demyelination.

“Cortical demyelinating lesions became associated with progressive forms of the disease,” says Caterina Mainero, MD, PhD, from the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston.

High-Strength MRI
The relevant lesions, however, have often been undetectable with conventional-strength MRI. MRI of the lesions poses challenges, especially with 1.5 T or even 3 T scanners—specifically, most lesions are missed. “The number of lesions seen on MRI is considerably lower than that reported by neuropathological examinations,” Mainero says.

That information compelled Mainero and colleagues to investigate the viability of ultrahigh-field 7 T MRI, which, with more than twice the magnetic field strength, offers greater sensitivity than 3 T systems. This presented an opportunity: Could more advanced MRI better detect cortical lesions in patients with MS and distinguish the different histopathological types of cortical lesions described by neuropathology?

“MRI is already of paramount importance for early diagnosis of MS, for monitoring treatment response in clinical practice and experimental trials, and for investigating disease pathophysiology,” Mainero says. “Use of 7 T MRI can offer improved sensitivity for monitoring cortical pathology in the disease.”

Mainero and her fellow researchers conducted and published several cross-sectional studies demonstrating that cortical lesions frequently can be seen in patients with MS, from the earliest disease stages, at a higher rate than lower-field MRI. Furthermore, it appeared evident that newly visible lesions strongly correlate with neurological disability. The researchers’ study, “Longitudinal Characterization of Cortical Lesion Development and Evolution in Multiple Sclerosis with 7.0-T MRI,” was recently published in Radiology.

“We were interested to see what causes cortical lesion development in MS, how quickly these lesions accumulate in MS—especially related to white matter—and how do cortical and white matter lesions contribute to neurological disability,” Mainero explains.

The main objectives were as follows:

• to characterize the development and evolution, over a mean interval of 1.5 years, of cortical lesions across different regions of the cortex; and
• to investigate the rate of cortical lesion accumulation, its relationship with the rate of accrual of white matter lesions, and the contribution of cortical and white matter lesions to disability progression.

“We were specifically interested to assess whether cortical lesions mainly develop in grooves on the brain’s surface called sulci,” Mainero says. “This finding would suggest a possible link between cortical lesion development and a neuroinflammatory process mediated by cerebrospinal fluid, the flow of which may be restricted in the sulci.”

The 7 T MRI scanner best served the researchers’ purpose. A 7 T scanner provides better spatial resolution and a higher signal-to-noise ratio (SNR) than lower field strength MRI [1.5 T or 3 T] systems, Mainero explains. This is especially relevant for the study of small and thin brain structures such as the cortex.

“The SNR was further improved by the use of multichannel radiofrequency technology,” she adds, noting that the Siemens Human scanner was used.

As far as the study’s patient population, the researchers included both relapsing-remitting MS patients—the most common disease course characterized by clearly defined attacks of new or increasing neurologic symptoms—and secondary progressive MS patients. The latter set of patients demonstrate more advanced disease characterized by more significant disability. The study involved more than 40 subjects: 20 patients demonstrating the relapsing-remitting type of MS, wherein symptoms either improve or worsen; 13 patients with secondary-progressive MS, the form characterized by more severe disability; and 10 control subjects.

Tracking Lesions
The study’s results provide new and valuable information about diagnosis, tracking, and subsequent treatment. It became evident during the research that a strong predictor of substantial neurological disability occurred in the brain’s gray—cortical—area. Twenty-five patients (80%) developed new cortical lesions, as revealed by 7 T MRI. Detection proved far higher than in previous studies that used lower-field-strength MRI iterations. Mainero says an important take-home point was that, on average, lesion numbers developing in the cortical region were more than double the amount that developed in the brain’s white matter.

“We found that 80% of patients developed new cortical lesions,” Mainero reveals. “The number of new cortical lesions was more than twice the number of lesions that developed in the white matter. Based on the higher rate of accumulation, we found that cortical lesions were the strongest predictor of disability progression in our MS cohort.”

In addition, the researchers found that new cortical lesions were indeed most frequently located in the sulci. “This suggests that cortical lesion formation is influenced by some pathogenetic mechanisms present at the sulcal level,” Mainero says.

Scans showed that lesions accumulated and developed in the sulci, which present a complex landscape in the cerebral cortex. This landscape includes folds, grooves, and fissures of varying sizes and degrees. Previously, these indentations held secrets; sometimes, the secrets were deep and dark.

Now revealed, the accumulation and development in sulci enable better predictors of a patient’s possible disability. Also, the reasons for the accumulating lesions in this region are still not definitive, but much has been discovered. Researchers have observed that cerebrospinal fluid flow is very likely restricted in these areas, and the flow of such fluid, which surrounds the spine and brain, causes the sulci to become more susceptible to inflammatory response.

The findings led to the next question: What will be the impact of this research? “Our study adds to other recent investigations on the presence and impact of cortical lesions in MS, and strongly indicates that cortical lesions are clinically relevant,” Mainero says. “Their monitoring should be included in evaluating patient progression and become a goal of treatment strategies.”

Although the results fostered optimism, “our findings need to be replicated in larger MS cohorts,” she says.

Also, while 7 T MRI usage can offer improved sensitivity for the MS challenge, a technical issue reared its head. “Ultrahigh-field-strength imaging at 7 T remains technically challenging and too expensive for large-scale clinical deployment,” Mainero says, but she adds that a new 7 T system, Siemens’ MAGNETOM Terra, has been recently released for clinical use in Europe and the United States. Even so, it’s important to standardize imaging protocols across different centers and platforms for reliable usage in large clinical settings, she points out.

Mapping a Path Forward
Meanwhile, Vasily L. Yarnykh, PhD, an associate professor and associate director of the Bio-Molecular Imaging Center in the department of radiology at the University of Washington in Seattle, has conducted research in a similar direction. Specifically, he is developing a method that enables MRI mapping of a subject’s brain to visualize myelin. He has noted the erosion of the myelin protective layer, which negatively impacts neuromuscular functionality. With quantitative measurements of such erosions, clinicians could have an indicator of therapy effectiveness.

Yarnykh explains that the myelin factor led him in this research direction. “Until recently, the focus was on inflammation,” he says, “but now we’ve seen objective quantitative indicators.”

These factors became apparent through MR imaging. “We were looking for indicators that would quantify the amount of myelin and the process leading to its loss and its recovery,” he describes. The overall purpose of such quantification is to identify an objective number, not just an image. Gleaned information could then be used in determining a clinical decision. Yarnykh concedes that more research needs to be done, but he says quantification represents a very promising direction.

In developing protocols, Yarnykh has used MRI equipment from scanners developed by major vendors—General Electric, Philips, and Siemens. While conducting his research, he received the National Institutes of Health High-Impact Neuroscience Research Resource award, a $700,000 grant that has helped to increase the availability of myelin measurement methodology and equipment for research and clinical sectors.

Across the ocean, researchers at University College London and King’s College London embarked on an effort to use AI for detection of brain response to MS treatment. Their research resulted in a method that has significantly higher sensitivity than conventional radiologic approaches.

The research team studied a population that included those with relapsing-remitting MS treated with natalizumab, an approved drug used in the treatment of patients with relapsing MS. It is prescribed to forestall symptomatic episodes and increasing disability. MRI scans were taken before and after treatment initiation, providing more detailed information.

Furthermore, “imaging fingerprints” were extracted from each serial scan, which captured yet more details about changes in white and gray matter. This AI-assisted modelling could compare pre- and posttreatment with greater accuracy than conventional imaging analysis. Researchers indicated that this novel approach could help to better guide individual patient therapy and more rapidly determine treatment success or failure. In addition, the approach could be used in new drug trials.

Beyond MS
All researchers seem to agree that these new innovative approaches need not be restricted to MS.

“MRI has provided and is continuing to provide relevant information on in vivo pathogenetic mechanisms of disease in a wide variety of disorders of the central nervous system,” Mainero says. “There is no doubt that its usage will be applied in many brain disorders other than MS.”

Yarnykh says that more information about myelin levels could be a strong indicator of treatment effectiveness, therapy, and tissue recovery in patients suffering traumatic brain injury or stroke. As he points out, stroke involves death of brain tissue—neurons and glial cells—and it disrupts myelin. He emphasizes that it’s important to measure demyelination and remyelination, as these processes can be in competition.

Yarnykh adds that there is potential to measure brain development in children. The potential age range would include infants and adolescents. He explains that myelin develops very early in life; if a child’s neural development appears problematic, effective myelin measurement could provide crucial information.

“This would be a major coup because newborns have a very small amount of myelin in their brains,” he says. As such, an analysis would involve tracking myelin development in at least the first two years of life. This could provide a treasure trove of information in relation to neurological development.

The next immediate step in this direction is more research. Investigators are looking to replicate their data in larger populations, an effort that will yield more information about lesion accumulation and inflammatory response.

“Our study adds to other recent investigations on the presence and impact of cortical lesions in MS,” Mainero says. She adds that recent studies strongly indicate lesions are clinically relevant, and their monitoring should be included in evaluating patient progression and become a goal of treatment strategies.

— Dan Harvey is a freelance writer based in Wilmington, Delaware.