In April, Buffalo Neuroimaging Analysis Center (BNAC) Director Robert Zivadinov, MD, PhD, presented a poster at the American Academy of Neurology’s Annual Meeting describing a new, Novartis Pharmaceuticals-funded study to assess the effect of siponimod, compared to ocrelizumab, on reactive microglia/astrocytes—a biomarker for active secondary-progressive multiple sclerosis (SPMS). And while the sponsor’s interest focused on comparing disease progression in the siponimod (microglia-targeted) therapy vs. the ocrelizumab (anti-inflammatory) therapy, the study highlighted the critical need for accurate measures of microglia activation.

In a recent University at Buffalo’s Department of Neurology “Grand Rounds” presentation to research colleagues, doctoral candidates, and other students, Zivadinov provided a more comprehensive discussion of how a combination of traditional and novel imaging methods open the door wider to targeting microglia activation as a viable MS therapy. New imaging methods used in the study make it possible or easier to reliably assess microglia activation in living patients in addition to guiding pharmaceutical companies developing new microglia-focused MS treatments.

Put more simply, Zivadinov and his BNAC colleagues are delivering therapy-accelerating imaging of microglia activation, a long-trusted but hard-to-measure biomarker for secondary-progressive multiple sclerosis (SPMS). Currently it is not possible to predict who will eventually develop SPMS in which lost or damaged nerves worsen MS symptoms.

“This is a perfect example of where advancements in imaging itself can accelerate the pursuit of a cure for MS,” said Zivadinov. “So much of our work is connecting new approaches to existing knowledge in ways that move the science forward.”

Microglia as Therapeutic Targets

Microglia are a specialized population of central nervous system cells that are vital to a healthy immune system. They are considered immune “sentinels” and perform many functions that protect other cells in the central nervous system.

Yet, while microglia help even in MS patients, they can go wrong—becoming abnormally activated—and actually facilitate disease progression. While this has been understood for two decades, conventional MRI techniques, while very good at detecting multiple forms of lesions—the loss of brain matter easily detected using traditional MRI—they are not adequate in detecting microglia activation. This is partly because brain atrophy itself does not indicate which lesions experience microglia activation and its adverse effects.

The key may lie in understanding chronic active lesions (CALs), a specific type of lesion—brain injury or disease—that show chronic axonal damage, demyelination, and evidence of persistent neurodegeneration. In autopsies, CALs have  been shown to represent as high as 40 percent of chronic MS lesions and we know that CALs have very few immune-supporting microglia. Therefore, learning more about the presence of microglia in certain parts of CALs could point toward new therapies that influence microglia activation and a positive impact disease progression.

In conjunction with the 2022 ACTRIMS Forum, Zivadinov took part in a Feb. North American Imaging in Multiple Sclerosis (NAIMS) workshop that generated a consensus statement on CALs. This discussion further advanced a shared understanding of the characteristics of CALs, including some that are “missed” by conventional MRI techniques.

Consistent with this consensus understanding of CALs attributes, the BNAC microglia study addresses CAL attributes including paramagnetic rim lesions (PRLs), slowly expanding lesions (SELs), and PET ligand binding. Accordingly, the study employs four imaging modalities: 1) quantitative susceptibility mapping to measure paramagnetic rim lesions; 2) mapping slowly expanding lesions over time using conventional MRI sequences; 3) positron emission tomography (PET) using an extremely sensitive translocator binding benzodiazepine receptor protein called 18F-PBR06 to detect binding in lesions, perilesional tissue, or normal-appearing white and gray matter; and 4) use of ferumoxytol (Feraheme™). Ferumoxytol, a treatment for anemia, is an FDA-approved agent similar to gadolinium, which could be used in MS clinical trials to enhance MRI contrast in lesions.

Powerful When Taken Together

During Grand Rounds, Zivadinov explained the strengths and weaknesses of each method, which alone, render their value limited or even inadequate in understanding microglia activation. Yet taken together, the four methods reveal a compelling new picture. Detailed comparisons of various imaging techniques associated with these methods remain to be done.

The NAIMS consensus statement also addressed methods of analyzing images, allowing for further progress using automated detection techniques along with statistical methods including artificial intelligence. Zivadinov noted that reliability of these techniques in the future will require the use of BNAC’s and others’ large datasets and multi-center studies.

The discussion is another indication that BNAC remains at the forefront of imaging methodology and the search for a cure for MS.

“There are moments during our years of pursuing meaningful progress in MS and other imaging research when complementary factors come together… when it feels like our work lurches forward to new understandings with broad implications,” said Zivadinov. Our work on microglia, alongside contributions from colleagues around the world, feels like one of those moments.”

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