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  • Molecular probe detects early signs of MS

Feb 2014
SAN FRANCISCO – A new fluorescence-based molecular probe can detect multiple sclerosis (MS) at its earliest stage – even before the onset of physical signs.

MS develops when the body’s immune system attacks the protective myelin sheath that surrounds nerve cells. This leads to symptoms including numbness, fatigue, difficulty walking, paralysis and loss of vision. Some drugs can delay symptoms but do not treat the underlying causes, which researchers are only just beginning to understand.

For some, MS attacks slowly and progressively over many years; for others, it strikes without warning in fits and starts. But all patients share one thing in common: The disease was long present in their nervous systems, hiding under the radar from even the most sophisticated detection methods as it developed.

A new study from Gladstone Institutes researcher Dr. Katerina Akassoglou shows in animal models that heightened activity of a protein called thrombin in the brain could serve as an early indicator of MS. By developing a fluorescent probe specifically designed to track thrombin, the team found that active thrombin could be detected at the earliest phases of MS, and that it correlates with disease severity.

Using advanced detection and imaging techniques, Gladstone scientists were able to track thrombin activity in mice modified to mimic MS (left) compared to healthy controls. Courtesy of Dimitrios Davalos/Kim Baeten/Katerina Akassoglou, Gladstone Institutes.

Last year, Akassoglou and colleagues found that a key step in the progression of MS is the disruption of the blood-brain barrier. If the barrier breaks down, a blood protein called fibrinogen seeps into the brain. When this happens, thrombin responds by converting fibrinogen into fibrin, a protein normally not present in the brain. As fibrin builds up, it triggers an immune response that leads to the degradation of the nerve cells’ myelin sheath, over time contributing to the progression of MS.

“We wondered whether thrombin activity could in turn serve as an early marker of disease,” said Akassoglou, who directs the Gladstone Center for In Vivo Imaging Research (CIVIR). She is also a professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. “In fact, we were able to detect thrombin activity even in our animal models, before they exhibited any of the disease’s neurological signs.”

In lab experiments on mice modified to mimic the signs of MS, the team employed an activatable cell-penetrating peptide (ACPP), a molecular probe that delivers fluorescent agents to a region of interest. For this study, they developed a thrombin-specific ACPP that can track thrombin activity in mice as the disease progresses. They then carefully analyzed where – and at what stage of disease – thrombin activity was found.

“We detected heightened thrombin activity at specific disease ‘hot spots,’ regions where neuronal damage developed over time,” said Dr. Dimitrios Davalos, a Gladstone staff research scientist and associate director of the CIVIR. “And when we compared those results to those of a separate, healthy control group of mice, we saw that thrombin activity in the control group was wholly absent.”

The findings, reported online in Annals of Neurology (doi: 10.1002/ana.24078), could spur the development of a much-needed early-detection method for MS, and help doctors monitor treatment and disease progression, the team said.

The emission of light or other electromagnetic radiation of longer wavelengths by a substance as a result of the absorption of some other radiation of shorter wavelengths, provided the emission continues only as long as the stimulus producing it is maintained. In other words, fluorescence is the luminescence that persists for less than about 10-8 s after excitation.
Acronym for profile resolution obtained by excitation. In its simplest form, probe involves the overlap of two counter-propagating laser pulses of appropriate wavelength, such that one pulse selectively populates a given excited state of the species of interest while the other measures the increase in absorption due to the increase in the degree of excitation.
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