Commentary

Article

NeurologyLive
Summer 2024

MS Biomarkers: Overview of Current and Emerging Markers

This article reviews emerging MRI, OCT, CSF, and blood biomarkers, highlighting their potential roles in improving MS patient management and prognosis.

Asya Wallach, MD

Asya Wallach, MD

A biomarker is any number of medical signs that can provide objective evidence of the state of a disease.1 In the context of multiple sclerosis (MS), these may be anatomical data from MRI andoptical coherence tomography (OCT), and liquid biomarkers from cerebrospinal fluid (CSF) and blood.

This article will attempt to provide an overview of some emerging markers of interest to clinicians involved in treating the MS patient population. These biomarkers are at varying stages of use in the clinic, but understanding their utility, and ultimately their role in the care paradigm, will be critical to ensuring their effective employment in patient monitoring and disease management.

Magnetic Resonance Imaging

MRI is the most routinely used diagnostic tool for MS. A lesion count of greater than 20 T2 lesions at baseline and an infratentorial/spinal cordlesion location are suggestive of a worse prognosis.2 We routinely perform MRIs of the brain in treating patients with MS3; new lesions or contrast-enhancing lesions are a biomarker of active MS, and lesion volume growth and total white matter lesion volume growth are associated with increased disability progression.2

Current MS neuroimaging research is focused on identifying and understanding the clinical importance of chronic lesion activity in the form of slowly expanding lesions and paramagnetic rim lesions, which appear to be predictors of disease progression4; the central vein sign, which helps differentiate MS vs non-MS5,6; and automated volume measurements of whole brain, deep gray matter, cortical gray matter, and the cervical cord.7

Optical Coherence Tomography

The visual pathway is frequently affected in individuals with MS. OCT is an ultrasound technique that has been used in MS treatment since 1999 to visualize the retina of undilated eyes and measure the thickness of the retinal nerve fiber layer (RNFL), which is a proxy for axonal neurodegeneration of the central nervous system (CNS). During an acute episode of optic neuritis, the RNFL thickness will increase (due to swelling);subsequently, RNFL thickness will decrease (due to resolution of the acute swelling and resultant atrophy). The RNFL is thinnest in MS eyes that have experienced optic neuritis but also thinner in MS eyes without a history of attack relative to healthy control eyes.8

OCT angiography (OCT-A) is a technique that is combined with OCT. It is a promising technology that helps to distinguish between MS, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody–associated disease, 3 conditions that can be difficult to differentiate given overlapping presentations.9 For a recent comprehensive review of OCT/OCT-A biomarkers in MS, see the article by Donica et al.9 

Cerebrospinal Fluid

Current diagnostic criteria for MS, the 2017 McDonald criteria,10 include CSF-specific oligoclonal bands (OCBs) as a possible supporting feature of the clinical diagnosis of MS. The presence of a higher count of CSF OCBs supports a worse prognosis.11 OCBs are evaluated in a labor-intensive technique and require a qualitative interpretation.A quantitative alternative, the CSF kappa free light chain, has emerged as a potential indicator of CSF-specific IgG production.12,13

Blood

Neurofilament light chain (NfL) is a biomarker of neuro-axonal injury, first identified in the CSF and later validated in serum. Serum concentrations are highest in patients with progressive MS relative to patients with relapsing MS and lowest in individuals deemed healthy controls.14 There is a prognostic value of baseline serum NfL (sNfL) levels; in 1 study of 3480 patients with 15 years of follow-up, patients with MS with baseline sNfL levels similar to those of healthy controls were 4.3 times less likely to develop a score greater than 4 on the Expanded Disability Status Scale, and they were 7 times less likely to develop progressive MS than those with elevated baseline sNfL levels.15

Successful disease-modifying treatment will reduce the sNfL level.14 NfL may be a useful marker in confirming disease stability, or lack thereof, such as when a patient mentions symptoms that may be compatible with a relapse or a pseudorelapse. However, it is essential to note that the kinetics of this biomarker are not well understood, and an elevated value may indicate an evolving or resolving attack. Additional caveats to consider when using sNfL are that although this biomarker is elevated in individuals with MS, it is not specific for MS. Elevations are possible due to neuronal injury in the CNS and peripheral nervous system. sNfLis elevated in cases of kidney disease, cardiovascular disease, smoking, aging, pregnancy, and COVID-19; it is decreased in cases of increased blood volume.16,17

Further, GFAP is a biomarker of astrocyte reactivity and damage. Elevated GFAP levels are predictive of increased disability status within 6 months among individuals with MS.18 Both sNfLand GFAP testing have recently become available via commercial laboratories and may proveinvaluable in understanding patient trajectories and personalizing treatment.

For more information on this topic, see the recent comprehensive review by Gill et al.18

REFERENCES
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13.Saadeh RS, Bryant SC, McKeon A, et al. CSF kappa free light chains: cutoff validation for diagnosing multiple sclerosis. Mayo Clin Proc. 2022;97(4):738-751. doi:10.1016/j.mayocp.2021.09.014
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16.Barro C, Chitnis T, Weiner HL. Blood neurofilament light: a critical review of its application to neurologic disease. Ann Clin Transl Neurol. 2020;7(12):2508-2523. doi:10.1002/acn3.51234
17.Verde F, Milone I, Bulgarelli I, et al. Serum neurofilament light chain levels in Covid-19 patients without major neurological manifestations. J Neurol. 2022;269(11):5691-5701. doi:10.1007/s00415-022-11233-5
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