Blood levels of GFAP protein may predict disease progression in PPMS

The ongoing worsening of disability among people with primary progressive multiple sclerosis (PPMS) may be predicted by elevated blood levels of the GFAP protein, a marker of damage to star-shaped support cells in the brain and spinal cord called astrocytes, a study suggests.

The risk of disability progression was nearly three times higher in PPMS patients with high GFAP levels, the data showed. Moreover, it increased to four times higher among patients who also had low levels of neurofilament light chain (NfL), a marker for nerve cell damage.

These findings suggest that testing both GFAP and NfL may help identify PPMS patients with less active disease and a particularly high progression risk, according to the researchers.

The team noted that “insufficient tools to evaluate the disease course are some of the critical limitations” of caring for those with progressive MS at this time.

The study, “Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis,” was published in the Annals of Clinical and Translational Neurology.

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Predicting progression a ‘significant unmet need’ in PPMS

MS is a chronic neurological disorder that affects the brain and spinal cord, marked by specific areas of damage, known as lesions, that can be seen on imaging scans. Such lesions disrupt the normal function of nerve impulses, resulting in a wide range of MS symptoms.

The majority of patients are initially diagnosed with relapsing-remitting MS (RRMS), in which periods of acute symptom worsening, called relapses, are interspersed with periods when symptoms ease or go away, or remission. These patients can then transition into a progressive form of the disease called secondary progressive MS (SPMS), in which the disease steadily worsens even in the absence of relapses.

In the alternate, about 1 in 10 patients will first be diagnosed with PPMS, characterized by a constant worsening of symptoms from disease onset, with or without relapses.

According to the researchers, based at the University Hospital of Ulm, in Germany, “progression prediction is a significant unmet need in people with progressive multiple sclerosis.”

EmBioProMS is an ongoing multicenter observational study in Germany that aims to define the association between novel blood biomarkers and disease progression in a well-characterized group of SPMS or PPMS patients.

As part of it, GFAP and NfL levels in blood samples were measured at least once for 243 participants, of whom 108 were diagnosed with SPMS and 135 with PPMS.

GFAP provides structure to astrocytes, cells that support nerve cell function, while NfL supports the structure of nerve fibers. With damage, these proteins are released from cells and can be detected at higher than normal levels in the blood and other body fluids.

Here, the researchers investigated if levels of these proteins in the blood were linked to confirmed disability progression in people with progressive MS.

Such disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) scores, in the time patients took to walk 25 feet (about 8 meters), or in a worsening of finger dexterity measured with the nine-hole-peg-test (9HPT), which was confirmed in a subsequent visit at least six months later.

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More lesions in brain, spinal cord linked to higher GFAP levels

Data showed that, at the study’s start, or baseline, individuals with progressive MS had significantly higher blood levels of GFAP and NfL compared with established reference values from healthy populations.

Elevated levels of these biomarkers were both associated with increased disability, either measured with the EDSS scale, the timed-25-foot walk test (T25FW), or the 9-HPT.

However, after adjusting for factors that may influence the results — including age at onset, sex, and disease duration — GFAP and NfL levels were only significantly associated with 9HPT time —that is, high GFAP and NfL were linked to worse finger dexterity.

From MRI scans, a higher number of lesions in the brain or spinal cord — specifically, more than eight lesions — significantly correlated with higher GFAP and NfL levels. Active inflammatory lesions also were significantly related to elevated NfL, but not GFAP.

Treatments appeared to have no effect on GFAP levels, while those given antibody-based therapies had lower levels of NfL, indicating these such medications could reduce nerve damage.

Among the 111 documented progression events occurring in 86 patients during follow-up, about half (52.3%) were seen as T25FW worsening. That was followed by 9HPT (36.0%), then EDSS progression (34.2%).

While elevated GFAP at baseline was not significantly associated with a higher risk for confirmed disability progression during follow-up in the entire population, high levels of this biomarker predicted a 2.88 times higher risk of disability progression in PPMS patients.

This study reports GFAP and NfL predictive value for combined outcome disability in a clinically defined PMS population. Our findings add to the promising, growing body of evidence regarding GFAP application regarding disability progression in MS.

The risk was even greater in PPMS patients with high GFAP and the lowest NfL levels, who had a 4.3 times higher risk for progression. Among SPMS patients, however, high GFAP values were not related to a higher risk of progression.

“The combination of high GFAP and low NfL levels might recognize a particular subset of [people with progressive MS] with distinct pathology [disease] and a high risk of progression,” the researchers wrote.

“This study reports GFAP and NfL predictive value for combined outcome disability in a clinically defined PMS population,” the team concluded. “Our findings add to the promising, growing body of evidence regarding GFAP application regarding disability progression in MS.”