A novel imaging approach enables assessment of key nervous system deterioration in multiple sclerosis (MS), a new study in mice suggests.
The research, “Development of a PET radioligand for potassium channels to image CNS demyelination,” was published in the journal Scientific Reports.
MS is characterized by damage to myelin (a process called demyelination), which is an insulating sheath around axons (the long projections of neurons) that enables effective neuronal communication. As a result, patients experience a variety of symptoms, including muscle stiffness and weakness, fatigue and pain. Although existing MS medications suppress immune responses and reduce flare-ups, none can cure the disease.
Despite the importance of demyelination in MS, scientists and clinicians do not currently have a way to directly image myelin damage. Magnetic resonance imaging (MRI) is used, but it does not enable the distinction between demyelination and inflammation, which are common in patients with MS.
Upon myelin damage, voltage-gated potassium channels (cellular membrane proteins) become exposed. As a result, cells leak potassium, which impairs proper neuronal communication. This prompted researchers to develop a tracer that targets potassium channels.
“In healthy myelinated neurons, potassium channels are usually buried underneath the myelin sheath,” Brian Popko, PhD, the study’s senior author, said in a press release. Popko is a professor of neurological disorders and director of the Center for Peripheral Neuropathy at The University of Chicago.
Exposed potassium channels can be targeted by the MS medication 4-aminopyridine (4-AP; dalfampridine), which partially repairs nerve conduction and mitigates MS symptoms.
Using mouse models of MS, the researchers demonstrated that 4-AP binding to potassium channels is greater in demyelinated axons in comparison with well-myelinated axons. The greater binding of 4-AP led to its accumulation in damaged axons.
Then, the team evaluated several fluorine-containing derivatives of 4-AP, and found that the most effective in binding to potassium channels was 3-fluoro-4-aminopyridine (3F4AP), which can be labeled with radioactive 18F. This labeling enables detection of demyelinated regions with a novel strategy based in positron emission tomography (PET).
“3F4AP is the first tracer whose signal increases with demyelination, potentially solving some of the problems of its predecessors,” said Pedro Brugarolas, PhD, first author of the study.
Existing PET tracers bind to myelin. This translates to decreases in signal in the presence of myelin loss, “which can be problematic for imaging small lesions” Brugarolas noted.
Importantly, the findings in mice were confirmed in monkeys. Experiments showed that the radiolabeled 3F4AP enters the primate brain and accumulates in areas with less myelin.
Collectively, “these data indicate that [18F]3-F-4-AP may be a valuable PET tracer for detecting [central nervous system] demyelination noninvasively,” the team wrote.
“We think that this PET approach can provide complementary information to MRI which can help us follow MS lesions over time,” Popko said.
The novel PET strategy enables the evaluation of therapies to repair myelination and also could help assess how much myelin loss is involved in other neurological disorders, such as traumatic brain injury and spinal cord injury, but also in diseases not commonly linked to demyelination, “such as brain ischemia, psychiatric disorders, and neurodegenerative diseases, including Alzheimer’s,” Popko concluded.