Emerging imaging and liquid biomarkers in multiple sclerosis

Abstract

The advent of highly effective disease modifying therapy has transformed the landscape of multiple sclerosis (MS) care over the last two decades. However, there remains a critical, unmet need for sensitive and specific biomarkers to aid in diagnosis, prognosis, treatment monitoring, and the development of new interventions, particularly for people with progressive disease. This review evaluates the current data for several emerging imaging and liquid biomarkers in people with MS. MRI findings such as the central vein sign and paramagnetic rim lesions may improve MS diagnostic accuracy and evaluation of therapy efficacy in progressive disease. Serum and cerebrospinal fluid levels of several neuroglial proteins, such as neurofilament light chain and glial fibrillary acidic protein, show potential to be sensitive biomarkers of pathologic processes such as neuro-axonal injury or glial-inflammation. Additional promising biomarkers, including optical coherence tomography, cytokines and chemokines, microRNAs, and extracellular vesicles/exosomes, are also reviewed, among others. Beyond their potential integration into MS clinical care and interventional trials, several of these biomarkers may be informative of MS pathogenesis and help elucidate novel targets for treatment strategies.

Keywords: Central vein sign; Glial fibrillary acidic protein; Neurofilament light chain; Optical coherence tomography; Paramagnetic rim lesion.

Figure 1:. Emerging MRI Biomarkers in MS: Central Vein Sign and Paramagnetic Rim Lesions.

A) White matter lesions in MS are acutely result of immune cell infiltration, particularly CD8⁺ T-cells, from the periphery into the CNS via small penetrating veins. These inflammatory lesions result in oligodendrocyte and myelin damage as well as neuro-axonal degeneration. After peripheral lymphocyte infiltration resolves a chronic demyelinated lesion centered around a vein remains B) Certain MRI sequences can depict white matter pathology and small CNS vessels simultaneously (e.g., T2*-weighted magnitude reconstruction; T2*-M). These small veins within classic ovoid MS lesions can be visualized and quantified to aid in MS diagnosis. Inserts show confirmation of central vein in two planes. C) Chronic active lesions in MS can be identified pathologically by an iron-rim at the lesion edge that contains iron-laden macrophages and microglia as well as activated astrocytes. D) These iron-rimed chronic active lesions can be visualized on MRI as paramagnetic rim lesions (PRLs) by “unwrapping” the phase reconstruction of the same T2*-weighted imaging (T2*-P). Paramagnetic rim lesions may represent a biomarker of at least one cause of progressive disease in MS. Created with BioRender.com

Figure 2:. Emerging Neuroglial Biomarkers in MS

Schematic of the CNS, periphery, and blood-brain barrier, and blood-CSF barrier cell types relevant to emerging neuroglial biomarkers and CSF-specific oligoclonal bands. Released neuroglial protein biomarkers are released from one or a select few CNS resident cell types where they can traffic to the CSF and blood. These cell-specific biomarkers may thus reflect cell-type specific pathology, such as axonal damage in the case of Nfl. Many neuroglial biomarkers also have identified or potential peripheral sources that may, if a significant source, limit or prevent the use of blood levels to be a useful as a biomarker, such as the case with parvalbumin and CHI3L1. Many neuroglial biomarkers cross the CSF-blood barrier and even the blood-brain barrier, particularly in the setting of blood-brain barrier injury such as occurs in an active MS lesion. This equilibrium between CSF and serum or plasma levels is important to determine for each biomarker as high peripheral levels from a non-CNS source may impact CSF levels requiring correction of obtained CSF values. Abbreviations: CHI3L1, chitinase-3 like protein 1; GFAP, glial fibrillary acidic protein; Nfl, neurofilament. Created with BioRender.com