GFAP protein levels in blood fail to predict disease progression in RRMS

Levels of GFAP protein in the blood — a marker of damage to support cells in the brain — were associated with the enlargement of brain lesions and of fluid-filled brain cavities called ventricles in people with relapsing-remitting MS (RRMS) undergoing Tysabri (natalizumab) treatment, a study showed.

While ventricular volume change can be used as an MRI biomarker for neurodegeneration and MS progression, a GFAP blood test may be a more convenient way to assess this change, according to researchers.

“A biomarker that could effectively monitor or even predict this enlargement in RRMS could be of great value,” the team wrote.

Despite these findings, GFAP was unable to predict the disease progression that occurs without relapses in Tysabri-treated RRMS patients, the study found.

The study, “Serum glial fibrillary acidic protein in natalizumab-treated relapsing-remitting multiple sclerosis: An alternative to neurofilament light,” was published in the Multiple Sclerosis Journal.

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Researchers cite need for progression-specific biomarkers in RRMS

MS is caused by an altered inflammatory response that damages parts of the central nervous system (CNS), which comprises the brain and spinal cord. Most patients are first diagnosed with RRMS, marked by relapses, or a sudden worsening of symptoms, followed by periods of remission when symptoms ease.

While relapse activity can worsen disability, a patient’s symptoms can progress without new relapses — even with treatment with highly effective disease-modifying therapies (DMTs) for MS. This form of disability worsening is referred to as progression independent of relapse activity (PIRA), or so-called silent progression.

However, it is challenging for clinicians to predict PIRA in treated RRMS patients due to a lack of progression-specific biomarkers.

Magnetic resonance imaging, known as MRI, has been proposed as a tool to monitor PIRA by measuring brain atrophy, a reduction in brain volume (shrinkage) beyond what normally occurs due to aging. Blood-based biomarkers are an alternative to MRI, offering a more accessible, convenient approach.

The glial fibrillary acidic protein, or GFAP, is a protein that provides structure to astrocytes — star-shaped cells that support nerve cell function. GFAP is mainly produced in the CNS, and elevated blood levels have been linked with nerve damage and brain atrophy in RRMS and secondary progressive MS.

To determine if this protein could serve as a biomarker of PIRA, a team of scientists based in the Netherlands measured GFAP levels in serum — the liquid portion of blood — from 88 RRMS patients. Blood samples were collected before and after these individuals received Tysabri, a DMT designed to prevent immune cells from accessing the CNS and causing inflammation.

The participants, of whom 75% were women, underwent MRI scans to assess lesions, look for signs of tissue damage and inflammation, and measure brain volumes. As a comparison, the team also evaluated neurofilament light chain (NfL), a well-established blood-based biomarker of nerve damage in MS.

Regardless of treatment, almost half of the patients (47.7%) showed significant disability progression over follow-up — defined as an increase in their Expanded Disability Status Scale (EDSS) score or a marked reduction in finger dexterity or walking function.

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No evidence to support GFAP protein levels as biomarker

Before treatment, those with lesions with active inflammation on MRI scans had significantly higher serum GFAP levels. With Tysabri, GFAP levels dropped significantly after three months and remained stable afterward in both progressors and non-progressors.

Blood tests measured at treatment start (baseline) and routinely over two years, however, failed to show a significant difference in GFAP levels between progressors and non-progressors. This finding remained after excluding those with relapses or MRI activity after one year of treatment, or adjusting for sex and disease duration at baseline.

[The results] suggest a role for sGFAP as tool for inflammation, treatment response, and radiological progression, but do not provide evidence supporting its use as biomarker for predicting and monitoring clinical progression in RRMS.

In MRI measures, a higher GFAP protein level over time was associated with a larger lesion volume after adjusting for in-between patient variation and correcting for age, gender, and MS duration. In addition, GFAP levels measured at baseline and 12 months were associated with the yearly change in the volume of brain ventricles, a result researchers noted as “interesting.”

“We found evidence that sGFAP and thus astrocytes are involved in not only active inflammation but also chronic processes such as brain atrophy,” the team wrote, adding, “This could indicate that astrocyte activity remains involved in MS lesions, independent of suppressing the transmission of inflammatory cells into the CNS.”

Like GFAP, NfL decreased significantly in the first three months of treatment but continued to decline for up to one year before its levels stabilized. No differences in NfL levels were seen between progressors and non-progressors over time. Baseline levels of GFAP correlated significantly with NfL, as did the last follow-up samples, and greater baseline NfL levels also were associated with the presence of active inflammatory lesions.

Unlike GFAP, NfL levels at baseline and 12 months were not related to volumes of lesions, the whole brain, or the ventricles.

These results “suggest a role for sGFAP as tool for inflammation, treatment response, and radiological progression, but do not provide evidence supporting its use as biomarker for predicting and monitoring clinical progression in RRMS,” the researchers concluded.