Advances in brain imaging are making it possible to visualize early and ongoing events in multiple sclerosis (MS) — beginning with the first signs of inflammation caused by immune cells entering the brain.
Should the new technique become available to physicians, it likely will not only allow for more precise diagnoses, but also for tracking the impact of treatments, both in a clinical setting and when developing new drugs.
The study, “Imaging Matrix Metalloproteinase Activity in Multiple Sclerosis as a Specific Marker of Leukocyte Penetration of the Blood-Brain Barrier,” is the cover story of the latest issue of the journal Science Translational Medicine.
Physicians now can examine the consequences of brain inflammation through magnetic resonance imaging, commonly known as MRI. These scans point to changes in brain tissue caused by inflammation, and are an invaluable tool in MS diagnosis, treatment, and research.
But MRIs only show damage that is already present. Scientists from the University of Münster in Germany built on their previous work to create an imaging method that can show inflammation as it happens.
The team in that earlier work had discovered that enzymes, called MMPs (matrix metalloproteinases), are crucial for enabling immune cells to cross the blood-brain barrier. This barrier is a lining of tightly connected cells that prevent most compounds, and usually also immune cells, from leaving blood vessels and entering the brain.
Mice lacking MMP-2 and MMP-9 do not develop the mouse version of MS, known as EAE (experimental autoimmune encephalomyelitis). So to better understand how the enzymes contribute to the initiation of disease, the team created a molecule that could be used to visualize the two MMP enzymes in mice.
This approach was made possible using a drug that binds to MMPs in order to block them, and linking that drug to a fluorescent dye. As the drug finds all the active enzymes in the body and binds to them, researchers could examine the workings of the enzymes at different stages by looking for their fluorescent light signals.
The experiments paid off. Microscopic evaluation of the mice brains were revealing. “We found that our observations of MMP activity provided precise information on where immune cells penetrate the blood-brain barrier and where inflammation occurs in the brain,” Dr. Hanna Gerwien, a molecular biologist and the study’s first author, said in a news release.
But the human skull prevents any analysis of light-emitting molecules, so the team then developed another version of the imaging factor. Making use of a weakly radioactive tracer molecule, the researchers turned the MMP blocker into a compound that can be used to visualize structures using positron emission tomography (PET). Since mice experiments were promising, they performed another small set of experiments on five patients having an acute MS relapse, and two control patients.
They discovered that the method could show ongoing inflammation before MRI-detectable brain lesions occurred. The signal also became weaker as patients received treatment.
“MMPi-PET therefore allows monitoring of the early steps of MS development and provides a sensitive, noninvasive means of following lesion formation and resolution in murine EAE and human MS,” the researchers concluded.