New PET Probe for Myelin in MS

Pauline Anderson

October 11, 2013

Researchers have developed and are testing a promising new imaging technique that could eventually help diagnose and monitor treatment in patients with multiple sclerosis (MS).

New evidence in mouse models showed that the target-specific molecular probe, which uses positron emission tomography (PET) imaging, can detect and quantify myelin damage as well as monitor the efficacy of drug treatments.

"This is a powerful tool that should eventually be used to diagnose multiple sclerosis patients much earlier, help in monitoring treatments aimed at myelin repair, and maybe help cure the disease," study author Yanming Wang, PhD, associate professor, radiology, and director, radiopharmaceutical program, Case Western Reserve University, Cleveland, Ohio, told Medscape Medical News.

The study was published online September 23 in the Annals of Neurology.

Myelin-Specific Tracers

For the past decade, researchers at Case Western have been developing myelin-specific radiotracers for in vivo PET imaging of brain myelin content and have identified several leading compounds that readily enter the brain and selectively localize in the myelinated white matter.

In pilot preclinical studies, one of these compounds, MeDAS, was radiolabeled with positron-emitting carbon II and was found to be a promising imaging marker of myelin.

The researchers showed that this compound can penetrate the blood–brain barrier and localize to brain regions in proportion to the extent of myelination. The marker was shown to quantitatively detect myelin changes in the brain in mouse models with myelin pathology.

Now, in a series of new animal experiments, the researchers demonstrated that MeDAS selectively stains myelin in the spinal cord and brain, proving that it is sensitive and specific for myelin.

In addition, PET studies in rat models showed that MeDAS uptake changes correlated with associated myelin loss in the spinal cord, demonstrating that the probe can detect and quantify myelin damage.

A third set of tests featured in their new publication showed that using MeDAS-PET can monitor the efficacy of myelin repair therapy with experimental hepatocyte growth factor, an agent being developed to restore myelin function.

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The probe specifically detects myelin damage independent of inflammation, said Dr. Wang. In MS, inflammatory damage accompanies myelin damage in the central nervous system, and inflammation is considered either the cause or a consequence of the disease. However, therapeutic approaches that modulate inflammation have had limited success.

Hallmark characteristics of MS are white and gray matter demyelination in the central nervous system. This demyelination leads to reduced axonal impulse conduction efficiency, which contributes to cognitive and sensory impairments and disability. Remyelination fails or is inadequate in MS, which leads to incomplete myelin repair and subsequent irreversible axonal damage.

Once myelin is severely damaged, there's not much that can be done to restore function, so it's important to find a way to zero in early on repairing myelin, said Dr. Wang. Researchers are aiming to do this, "but they need an imaging technique in place so they can monitor the effectiveness of new drugs."

Dr. Wang sees this new probe eventually being useful in diagnosing MS much earlier than is currently feasible, perhaps even at a presymptomatic stage. Today, MS can be diagnosed using behavioral tests but that takes time, and while MRI shows lesions in the brain and spinal cord, it doesn't distinguish between inflammation and demyelination.

"Myelin can be damaged years before patients develop symptoms, and this is very important for genetically affected individuals who may have a high risk of developing this disease but don't know when the onset would be," said Dr. Wang. "For any disease, early treatment is the key."

Patients who have family history of MS, particularly young females, should be monitored on a yearly basis, he added.

The new probe may also be used to monitor drug treatments, which should improve disease management.

"With such imaging technology, you can see the results within hours instead of days or months because it's a more direct and quantitative way to image in real time," said Dr. Wang. "You can just put the patient in the scanner, take an hour and a half and then get the results as to whether a drug works or not. If it works, the patient can be continued to be treated with it, and if it doesn't work, you can switch right away to another drug."

Dr. Wang and his colleagues are in the process of getting regulatory approval to initiate human clinical trials of this new probe.

"Really Exciting"

Invited to comment, Lily K. Jung Henson, MD, a neurologist specializing in MS at the Swedish Medical Center, Seattle, Washington, thinks the study is "really exciting" because current MRI technology is not very sensitive in terms of picking up spinal cord damage in MS.

"If this technique pans out, it allows us, at the very minimum, a complementary marker to assess demyelination in the spinal cord," said Dr. Jung Henson.

"If this imaging can be done in humans and correlates well with clinical activity, our ability to assess our patients' response to therapy — as well as diagnose those in whom imaging has not been able to identify pathology — will be greatly enhanced," she said.

This study was supported by grants from the Department of Defense, National Multiple Sclerosis Society, and National Institutes of Health. Dr. Wang has patents pending; another study author, Paul M. Mathews, MD, PhD, has part-time employment and stock-stock options with GlaxoSmithKline Research and Development.

Ann Neurol. Published online September 23, 2013. Abstract

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