An innovative PET tracer can measure damage from multiple sclerosis in mouse models

January 12, 2018, University of Chicago Medical Center
In healthy myelinated neurons, potassium channels are usually buried underneath the myelin sheath. When there is loss of myelin, these channels become exposed and leak intracellular potassium. This leaves them unable to propagate electrical impulses. Credit: Mayo Clinic

The loss or damage of myelin, a cellular sheath that surrounds and insulates nerves, is the hallmark of the immune-mediated neurological disorder multiple sclerosis (MS). When segments of this protective membrane are damaged, nerve impulses can be disrupted. Symptoms range from tingling and numbness to weakness, pain and paralysis.

There is currently no reliable way to directly image demyelination. Physicians rely on (MRI), but despite high resolution images, MRI is not quantitative and cannot distinguish between demyelination and inflammation, which often coexist in people with MS.

In the January 12, 2017 online issue of the journal Scientific Reports, a multi-institutional team based primarily at the University of Chicago Medicine and the National Institutes of Health, describe early tests of a novel minimally-invasive way to assess myelin damage using (PET).

These PET scans use a radioactive molecule designed to target voltage-gated potassium channels, a protein found on demyelinated axons. The PET images, based on the detection of this molecule, provide quantitative information about underlying biochemical processes.

"In healthy myelinated neurons, potassium channels are usually buried underneath the ," explained study author Brian Popko, PhD, 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."

These exposed neurons leak intracellular potassium. This leaves them unable to propagate electrical impulses, which causes some of the seen in MS. "So we developed a PET tracer that can target potassium channels," Popko said.

The team started with an existing MS drug, 4-aminopyridine (a.k.a. dalfampridine), which can bind to exposed potassium channels. This can partially restore nerve conduction and alleviate neurological symptoms in MS patients. Using mouse models of MS, including some developed in the Popko lab, the researchers showed that the drug accumulated in the demyelinated, or uncovered, areas of the central nervous system.

This approach has the potential to track responses to remyelinating therapies, an unmet need. It could also help determine how much disruption of the myelin sheath contributes to other central nervous system disorders.". Credit: University of Chicago Medical Center

Then, with help from colleague Pancho Bezanilla, PhD, professor of biochemistry and molecular biology at the University of Chicago, the team examined several fluorine-containing derivatives of 4-aminopyridine for binding to K+ channels. They found that 3-fluoro-4-aminopyridine (3F4AP) has the desired properties, so they labeled the molecule with fluorine-18, which is easily detected by PET.

"We were able to show, in rats, that the tracer accumulated to a higher degree in demyelinated areas than in control areas," Popko said.

"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 Pedro Brugarolas, PhD, first author of the paper and currently 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."

Finally, in collaboration with scientists at the NIH, the researchers conducted a study in healthy monkeys. They confirmed that radiolabeled 3F4AP enters the brain of primates and localizes to areas where there is little myelin.

"We think that this PET approach can provide complementary information to MRI which can help us follow MS lesions over time," Popko said. "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."

That list includes leukodystrophies, traumatic brain injury, spinal cord injury and "even maladies not traditionally associated with demyelination," Popko suggested, "such as brain ischemia, psychiatric disorders, and neurodegenerative diseases, including Alzheimer's."

"A tracer to monitor changes in something as ubiquitous as could have applications for other diseases where these channels are involved," Brugarolas added,

More than 2.3 million people worldwide suffer from multiple sclerosis, according to 2013 data from the MS International Federation. None of the 15 current FDA-approved drugs for MS are able to cure the disease; they modify or suppress the immune system, reducing the number and severity of flare-ups and less often, slowing the visible marks of brain damage.

Explore further: Pancreatic factor promotes remyelination in the central nervous system after injury

More information: Pedro Brugarolas et al, Development of a PET radioligand for potassium channels to image CNS demyelination, Scientific Reports (2018). DOI: 10.1038/s41598-017-18747-3

Related Stories

Pancreatic factor promotes remyelination in the central nervous system after injury

August 25, 2017
Brain functions are maintained by the neural network. Neural network is formed by the connection between the neurite, and this connection is supported by the wrapping of myelin. Demyelination is detected in the patients of ...

A little myelin goes a long way to restore nervous system function

October 24, 2017
In the central nervous system of humans and all other mammals, a vital insulating sheath composed of lipids and proteins around nerve fibers helps speed the electrical signals or nerve impulses that direct our bodies to walk, ...

How multiple sclerosis can be triggered by brain cell death

December 14, 2015
Multiple sclerosis (MS) may be triggered by the death of brain cells that make the insulation around nerve fibers, a surprising new view of the disease reported in a study from Northwestern Medicine and The University of ...

Model helps explain why some patients with multiple sclerosis have seizures

February 21, 2017
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that affects nearly 2.3 million people worldwide. MS is triggered when the immune system attacks the protective covering around nerve fibers, ...

Blood-clotting protein prevents repair in the brain

November 2, 2017
Picture a bare wire, without its regular plastic coating. It's exposed to the elements and risks being degraded. And, without insulation, it may not conduct electricity as well as a coated wire. Now, imagine this wire is ...

Recommended for you

Left, right and center: mapping emotion in the brain

June 19, 2018
According to a radical new model of emotion in the brain, a current treatment for the most common mental health problems could be ineffective or even detrimental to about 50 percent of the population.

Often overlooked glial cell is key to learning and memory

June 18, 2018
Glial cells surround neurons and provide support—not unlike hospital staff and nurses supporting doctors to keep operations running smoothly. These often-overlooked cells, which include oligodendrocytes and astrocytes, ...

Electrically stimulating the brain may restore movement after stroke

June 18, 2018
UC San Francisco scientists have improved mobility in rats that had experienced debilitating strokes by using electrical stimulation to restore a distinctive pattern of brain cell activity associated with efficient movement. ...

Neuroscientists map brain's response to cold touch

June 18, 2018
Carnegie Mellon University neuroscientists have mapped the feeling of cool touch to the brain's insula in a mouse model. The findings, published in the June 15 issue of Journal of Comparative Neurology, provide an experimental ...

iReadMore app improves reading ability of stroke patients

June 18, 2018
A new smart app designed to improve the reading ability of people who have suffered a stroke provides 'significant' improvements, a UCL study has found.

Brain matures faster due to childhood stress

June 15, 2018
Stress in early childhood leads to faster maturation of certain brain regions during adolescence. In contrast, stress experienced later in life leads to slower maturation of the adolescent brain. This is the outcome of a ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.