Bringing Focus to a Blurry Diagnosis

800px-pikiwiki_israel_15788_subtle_diagnosisDiseases, unfortunately, don’t come with an easy-to-read label. Physicians spend much of their time decoding their patient’s list of symptoms and a variety of examination and test results into a proper diagnosis, in order to determine the best possible treatment. The degree of difficulty is even higher for neurological diseases, where the intricacy of the brain can produce maddeningly vague symptoms. If a patient comes in complaining of dizziness, fatigue, headaches, and numbness, hundreds of conditions could be in play for the diagnosis, ranging from mere stress to a brain tumor.

Multiple sclerosis is one such disease of the nervous system where the boundaries of diagnosis can be frustratingly fuzzy. In addition to vague symptoms, MS “attacks” can be short in duration or spread out, with months or even years of disease-free living in between. Neurologists have some tests they can perform to look for signs of MS, but many cases lie on the borderline, and some patients find themselves bouncing from clinic to clinic seeking a definitive diagnosis.

“It’s still hard to diagnose MS, because there’s no single test,” said Anthony Reder, professor of neurology at the University of Chicago Medicine. “You need an MRI, maybe a spinal tap, a clinical exam, and a really good history. Sometimes we’re pretty sure that someone has MS, but there are people who don’t have many attacks, or the symptoms aren’t quite right, or the MRI is not quite right, or the spinal tap is negative. In those people, we are sometimes unsure.”

To clear up this uncertainty and help physicians make a faster, more definitive diagnosis, University of Chicago Medicine researchers are seeking “biomarkers” that can distinguish MS from other, similar diseases. Building from nearly 20 years of experience with beta-interferon, the first approved treatment for MS, Reder and colleagues have found a particular cellular signal that is commonly associated with multiple sclerosis. With a four-year, $850,000 grant from the National Multiple Sclerosis Society, the researchers are working on a blood test that could serve as an inexpensive way of diagnosing and predicting the future of MS…and even assist doctors in choosing the right treatment for each patient.

Reder and collaborator Xuan Feng, research associate (assistant professor) at University of Chicago Medicine, searched for a biomarker by looking at how beta-interferon works as an MS treatment. Interferons are natural factors involved in the body’s immune response to viral infection, and are known to regulate the expression of certain genes. By focusing on the beta-interferon pathway in MS sufferers and controls, the researchers found an intriguing difference at the level of a transcription factor called STAT1. In people with multiple sclerosis, STAT1’s activity is reduced, particularly during attacks and disease progression.

Further lab experiments found that this deficient STAT1 activation can be explained by a subtle protein modification: the phosphorylation of a particular serine on the STAT1 transcription factor. A blood test of untreated patients with MS will often find low levels of this phopho-serine, a deficit that can be reversed by treatment with interferon. The drug response — or lack thereof — can also predict whether the treatment is working to prevent attacks in a given patient, Reder said.

“We found that we can measure these interferon responses with the phospho-serine marker and the genes and proteins that it regulates,” Reder said. “For stable patients who are on therapy, the ones who have a good response are going to stay stable. The ones who have minimal response, even though they are stable then, are much more likely to have an attack within six months.”

In a recent paper published by Journal of the Neurological Sciences, a team led by Feng also looked at how the biomarker can help distinguish between MS and a similar disease called neuromyelitis optica, or NMO. Patients with NMO display a sort of false MS, with many of the clinical characteristics of multiple sclerosis. But the disease is caused by a different underlying issue (closer to what’s seen in lupus rather than MS) that can actually be worsened instead of helped by interferon treatment. Thus, for these patients, a correct and precise diagnosis is doubly important.

Fortunately, Feng and her colleagues found that their assay for serine-phosphorylated STAT1 (P-S-STAT1) could distinguish between the two diseases in a study using previously diagnosed patients. When stimulated with beta-interferon, the samples from NMO and lupus patients showed a larger P-S-STAT1 response compared to the response seen in samples from MS patients. With additional information from expression levels of STAT1’s genetic targets, making up an “interferon signature” for the diseases, the researchers could accurately sort the patients to their appropriate diagnosis.

“The interferon signatures were important in differentiating among these three diseases,” Feng said. “We identified MS as the only time those signatures are lower. In NMO, it’s higher. NMO is actually more active like lupus, not MS. That can help us to understand why this disease occurs, and why, unlike MS, interferon is not a therapy for NMO.”

Beyond the original diagnosis, the researchers are hopeful that these biomarkers can be used to track whether treatment is working in individual MS patients. Currently, assessing a drug’s effectiveness is tricky, due to the intermittent nature of MS attacks. Disease status can be monitored via MRI, but those scans can miss subtle changes, and aren’t cheap, costing thousands of dollars each time.

“There is one attack every two years in the average MS patient. That’s forever,” Reder said. “You can’t put somebody on therapy for two or three years and then decide whether they’re responding. It can appear to be an inactive disease, but there could be a lot of sub-clinical attacks that are not noticed.”

A laboratory test for P-STAT1 activity or other biomarkers can assess whether interferon is effective at restoring the patient to normal levels. If interferon doesn’t work on the lab bench, an alternate MS drug (such as natalizumab, glatiramer, or fingolimod) can be started instead, saving a patient months or even years on an ineffective treatment. Such a “practice run” could help patients get on the right treatment track earlier in their disease, helping them avoid attacks and delay or prevent disease progression. It may even improve their long-term prognosis. Recent research from the University of Chicago Medicine showed that MS patients who started interferon therapy early lived longer on average than those who started treatment late.

“Everybody’s looking for the one marker that will tell you who’s going to do well with therapy or without, and the marker that will predict whether you respond to ‘Drug X’,” Reder said. “If we can predict whether they’re good interferon responders, based on our test, you’d know how well people responded to the drug and can tell them, ‘This is good news.'”

[Photo by Elisha Barmeir/Wikimedia Commons]

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Feng X, Reder NP, Yanamandala M, Hill A, Franek BS, Niewold TB, Reder AT, & Javed A (2012). Type I interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis. Journal of the neurological sciences, 313 (1-2), 48-53 PMID: 22036215

About Rob Mitchum (512 Articles)
Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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