Patients with multiple sclerosis (MS) suffer from a loss of the protective sheath, known as myelin, which coats nerve fibers. While this demyelination disrupts nerve impulses and leads to the characteristic symptoms of MS – including numbness, weakness, pain and potential paralysis – there is no consistent way to visualize this loss of myelin.
Currently, magnetic resonance imaging (MRI) is used to determine the extent of demyelination, however it’s not a quantitative imaging technique and can mistake inflammation for demyelination. Since MS is an immune-mediated neurological disorder, patients often display some level of inflammation which can complicate MRI imaging.
Now, researchers at the University of Chicago Medicine and the National Institutes of Health (NIH) have developed a positron emission tomography (PET) tracer to help determine the level of demyelination using the imaging technique. The PET tracer – the details of which were published in the journal Scientific Reports – could be a minimally-invasive way to more accurately assess the damage done to the myelin sheath.
The PET tracer itself is a radioactive molecule which targets voltage-gated potassium channels found on demyelinated axons of nerve cells. Unlike MRI, PET imaging using this tracer molecule is quantitative.
“In healthy myelinated neurons, potassium channels are usually buried underneath the myelin sheath,” said Dr. Brian Popko, the Jack Miller Professor of Neurological Disorders and director of the center for peripheral neuropathy at the University of Chicago. “When there is loss of myelin, these channels become exposed. They migrate throughout the demyelinated segment and their levels increase.”
Stripped of their protective myelin coating, neurons become leaky. This leak makes them lose potassium, leading to weakened electrical impulses and the characteristic symptoms of MS.
In developing their PET tracer, the researchers sought to repurpose a drug designed to lessen some of the neurological symptoms of MS. This drug, known as dalfampridine (4-aminopyridine), accumulates in demyelinated nerve cells, according to the results of animal studies.
The study investigators found that 3-fluoro-4-aminopyridine (3F4AP) – a fluorine-containing version of the drug – bound most optimally to potassium channels, compared to other derivatives. By labeling the molecule with a radioisotope of the element, fluorine-18, they were able to use the drug as a tracer and detect it with PET.
“All existing PET tracers used for imaging demyelination bind to myelin and, consequently, demyelinated lesions show as decreases in signal, which can be problematic for imaging small lesions,” said Dr. Pedro Brugarolas, a faculty member at Massachusetts General Hospital/Harvard Medical School. “3F4AP is the first tracer whose signal increases with demyelination, potentially solving some of the problems of its predecessors.”
After collaborating on a non-human primate study with researchers at the NIH, Popko and his colleagues found that the PET tracer does travel to the brain and accumulate in non-myelinated areas. This means that the usefulness of 3F4AP could extend beyond tracking MS disease progression, helping physicians study traumatic brain injury and neurodegenerative diseases like Alzheimer’s.
“We think that this PET approach can provide complementary information to MRI which can help us follow MS lesions over time,” said Popko. “It has the potential to track responses to remyelinating therapies, an unmet need. This approach should also help determine how much disruption of the myelin sheath contributes to other central nervous system disorders.”