New Imaging Approach the Future of TIA Diagnosis?

January 12, 2017

A new understanding of processes involved in inflammation of the cerebral blood vessels during a transient ischemic attack (TIA) may eventually lead to a new diagnostic test for patients with this condition, French researchers say.

They describe studies in a mouse model of TIA showing that the inflammatory mediator P-selectin was overexpressed in the cerebral blood vessels. They used antibodies to P-selectin to manufacture imaging substrate that correctly identified animals with TIA by MRI.

"In this study, we provided the proof-of-concept that molecular MRI of P-selectin could be used to positively diagnose TIA by disclosing endothelial activation," the researchers conclude in a paper published in Brain.

"TIA is notoriously difficult to diagnose," senior author, Carine Ali, PhD, explained to Medscape Medical News. "A patient experiences sudden neurological symptoms but these are often transient so patients may not seek medical attention, and if they do, symptoms may have ceased by the time they get to hospital and even if an MRI is conducted quite often nothing shows up.

"There isn't a test that can tell if a patient has had a TIA," she added. "So it often gets missed. But it is important to diagnose as it can be a warning of an imminent stroke, which may be able to be prevented with aggressive medication and lifestyle change."

"Opportunity for Prevention"

In the paper, the authors note that stroke is the second cause of death worldwide and a leading cause of disability. As the population ages, stroke is predicted to cause 8 million deaths in 2030 and about 20% of patients with ischemic stroke have a preceding TIA. "Thus, TIA is a 'warning' event that provides an opportunity for prevention, and new guidelines highlight the need for urgent assessment of those patients," they state.

Professor Ali added: "We are missing this opportunity to prevent millions of strokes because we don't diagnose TIA effectively."

She and her team have been researching ways of detecting inflammation of the blood vessels in the brain that occurs during a TIA. She explained that the endothelium reacts to the ischemia by producing inflammatory markers.

"We wanted to investigate if we could identify which particular markers were elevated in TIA and whether we could detect them with a molecular imaging test."

Working with a mouse model of TIA, they found that P-selectin was elevated in these animals and that iron oxide particles containing P-selectin antibodies, after being injected into the blood, bound to the endothelium expressing this marker and was detectable on MRI.

"We are hopeful that these antibody particles can be developed for human use and become a clinically useful TIA test. Yes, there is a big jump to extrapolating these results to the clinic, but this is a promising finding which now needs to be studied further in humans," said Professor Ali.

Molecular MRI Is the Future

"This sort of molecular MRI is the future for the diagnosis of many conditions — not just in the brain but all over the body. In our study, P-selectin appeared to be specific for TIA, and the test was able to distinguish mice models of TIA from those of migraine or epilepsy."

In the paper, the authors note that microparticles of iron oxide offer important advantages for endothelial-targeted imaging. These include a size range that allows endovascular specificity because they are not taken up by endothelial cells and do not passively diffuse in the brain parenchyma, even with blood–brain barrier breakdown. They also result in strong hypointense contrast effects, which were evident for up to 48 hours after TIA in this study. That would be a reasonable timeframe to identify patients.

In an accompanying editorial, Phillip Zhe Sun, PhD, Cenk Ayata, MD, and Eng H. Lo, PhD, Massachusetts General Hospital and Harvard Medical School, Boston, say that a sensitive and specific ancillary diagnostic tool would enhance clinical management by identifying true TIAs for stroke prophylaxis in a timely fashion, and reduce unnecessary testing to rule out TIA mimics.

They note that more work needs to be done to investigate whether other neurologic conditions with vascular inflammatory changes could also be linked to vascular P-selectin upregulation, such as migraine with aura, vasculitis, and multiple sclerosis.

They also suggest that other endothelial surface molecules may also be involved, so there may be further opportunities to explore additional markers for a combinatorial approach.

But they conclude that the present study "represents an exciting and major step forward in the search for these elusive footprints and diagnostic biomarkers of TIA."

This study was funded by INSERM, Caen University, and the Regional Council of Lower Normandy.

Brain. 2016;140:146-157. Study full text, Editorial full text

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