Research on Biomarkers in Multiple Sclerosis

There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). New research published in JAMA Neurology suggests that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to serum neurofilament light chain (sNfL).

The pathogenesis of multiple sclerosis (MS) involves both adaptive and innate immune disease mechanisms. The former is associated with recurring episodes of acute neurologic symptoms, relapses, and formation of localized lesions in the brain and spinal cord caused by invasion of blood-derived immune cells. In contrast, the latter has been suggested to drive more diffuse inflammation and neurodegeneration, also called smouldering MS, that clinically presents as disease progression. Although high-efficacy therapies, such as B-cell–depleting treatment (BCDT), result in almost complete suppression of focal lesion formation, their effectiveness for preventing development of long-term disability is modest.

The long-term course of disability in MS is driven by two partly independent pathomechanisms: focal lesional activity and brain-diffuse neurodegeneration. Serum neurofilament light chain (sNfL) has been established in recent years as a biomarker of ongoing neuronal damage in the course of the former process, whereas its association with progression as the clinical manifestation of the latter is relatively weaker.

Glial fibrillary acidic protein (GFAP) is an intermediate filament of astrocytes, equivalent to NfL in neurons, and has been proposed as a biomarker to identify present disease progression and to prognosticate future progression in MS. Early studies measuring GFAP levels in the cerebrospinal fluid (CSF) of patients with MS found a correlation with neurologic disability in subsequent years; however, this was not the case for NfL levels. Furthermore, high CSF GFAP levels were found to be associated with faster progression to an Expanded Disability Status Scale (EDSS) score of 3 and 6, and levels were higher in primary progressive MS than in relapsing-remitting MS (RRMS).

In this cohort study conducted by Stephanie Meier et al, it is evident that sGFAP levels may serve as a biomarker that reflects specifically chronic disease processes conveyed by astrocytes that manifest as pure progression/PIRA in MS. With this property, sGFAP levels are complementary to sNfL, whose levels are strongly associated with neuronal damage due to lesional disease activity. Thus, sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Reference: Stephanie Meier, MSc^1,2,3; Eline A.J. Willemse, PhD^1,2,3,4; Sabine Schaedelin, MSc^1,2,3,4; et al
JAMA Neurol. Published online February 6, 2023. doi:10.1001/jamaneurol.2022.5250