Blood Proteins May Be Biomarkers for Diagnosis in Early NMOSD

GFAP, UCHL1 seen to shed into bloodstream in new study

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Glial fibrillary acidic protein (GFAP) and the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) enzyme appear to get shed into the bloodstream in the early stages of neuromyelitis optica spectrum disorder (NMOSD), a study found — suggesting that these blood proteins may one day be used to diagnose the autoimmune disease in humans.

If confirmed in additional studies, measurement of blood GFAP and UCHL1 levels could allow NMOSD patients to receive earlier and more adequate treatment, according to researchers.

The data also showed that combined with GFAP and UCHL1, neurofilament light chain (NfL), a marker of nerve cell damage, may be able to help doctors foretell an attack of symptoms and decide whether to continue or adjust ongoing treatment.

“Our study proposes novel options for diagnosing and monitoring the disease activity of NMOSD and provides new evidence related to NMOSD pathogenesis [disease development],” the team wrote.

The study, “Decipher potential biomarkers of diagnosis and disease activity for NMOSD with AQP4 using LC-MS/MS and Simoa,” was published in the journal International Immunopharmacology.

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Investigating blood proteins in NMOSD

NMOSD is a progressive autoimmune disease in which the optic nerve, which transmits signals between the eye and the brain, and the spinal cord (and to a lesser extent, the brain) become inflamed.

New or worsening symptoms, known as relapses, often occur without warning but may disappear altogether, sometimes without treatment. But some symptoms may persist, and more disabling relapses can follow.

Getting a diagnosis sooner, rather than later, can help doctors find the best treatment to ease the disease’s symptoms and keep future relapses from happening.

One way to reach a diagnosis is with blood testing to check for the presence of disease-causing autoantibodies such as those that target the water channel protein aquaporin-4 (AQP4). However, not all NMOSD patients will test positive for these autoantibodies.

As such, “there is a need for new biomarkers to meet clinical needs in diagnosis and monitoring,” the researchers wrote. This is especially true of blood biomarkers, given that their collection method is easier, more convenient, and less invasive compared with MRI or spinal fluid collection.

Now, a team of researchers in China used a technique called liquid chromatography–mass spectrometry/mass spectrometry (LC–MS/MS) to identify potentially new biomarkers of NMOSD.

This technique allowed them to determine the relative abundances of a list of proteins in brain tissue from a mouse model of NMOSD versus healthy mice.

The model developed the disease after receiving an injection of anti-AQP4 autoantibodies directly into the brain; the healthy mice were injected with healthy antibodies. In both groups, brain tissue near the injection site was collected for analyses.

The researchers found differences in the levels of 72 proteins: 31 were more abundant in brain lesions from mice with NMOSD-like disease, while 41 were less abundant than in healthy mice.

Of these, only four — GFAP, UCHL1, NfL, and tau — also were present in the animals’ blood samples.

All four proteins have been previously suggested as biomarkers of nerve cell damage. In addition, all have been shown to be involved in regulating the function of mitochondria, known as the powerhouses of cells.

Mitochondrial dysfunction has been implicated in several neurodegenerative diseases, including NMOSD.

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Searching for useful biomarkers in NMOSD

To confirm how useful these biomarkers could be, the researchers checked for their levels in blood samples from 29 NMOSD patients positive for anti-AQP4 autoantibodies.

These levels were compared with those of 13 people with myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD), 20 people with multiple sclerosis (MS), and nine healthy adults. MOGAD and MS are two other diseases in which the spinal cord and brain become inflamed.

More than 70% of patients in each of the three disease groups were experiencing a relapse when their blood was drawn. The remaining patients were in remission.

Results showed that both NfL and GFAP were significantly more abundant in blood samples from people with any of the diseases versus healthy adults. However, only UCHL1 was significantly more abundant in NMOSD patients than in those with MOGAD or MS, suggesting that it may be used to tell NMOSD from other similar diseases.

When the researchers looked at the blood levels of these biomarkers in the first two months of symptoms, they found that both GFAP and UCHL1 were significantly raised in people with NMOSD compared with the other groups.

This means that these two biomarkers may help in the diagnosis of NMOSD when the disease is still in its early stages.

Our study proposes novel options for diagnosing and monitoring the disease activity of NMOSD.

Further analyses showed that a combination of GFAP, UCHL1, and NfL was the best at distinguishing NMOSD patients during relapse from patients in the other disease groups, suggesting their potential to be used to monitor the disease over time.

After adjusting for potential influencing factors, NfL was the only biomarker significantly associated with the Expanded Disability Status Scale, a measure of disability, in NMOSD patients.

Also, blood levels of GFAP and NfL were significantly higher in NMOSD patients with brain lesions during a recent relapse, while those of UCHL1 were significantly increased in those with spinal cord lesions during a recent relapse.

These findings highlight that GFAP, UCHL1, and NfL may be potential biomarkers of AQP4-NMOSD, “and could be used to monitor disease activity,” the researchers wrote.

In addition, the data “retrieved a new connection between mitochondria dysfunction and NMOSD,” the team wrote, suggesting that mitochondrial dysfunction and its related proteins may be new therapeutic targets.

Still, larger studies are needed to further explore the diagnostic potential of GFAP, UCHL1, and NfL in NMOSD, the researchers concluded.