How biomarkers are helping with MS diagnosis and prognosis

A diagnosis of multiple sclerosis (MS) is relying more on biomarkers as experts aim to find it earlier and reduce the number of misdiagnoses, attendees at the Canadian Neurological Sciences Federation annual congress heard.The diagnosis of MS relies on the McDonald Criteria, updated in 2024 by a consortium of international experts (six of whom are from Canada) and published in October 2025. The new criteria include more of a focus on biomarker-driven diagnosis, explained Dr. Simon Thebault, a neurologist at the Montreal Neurological Institue and McGill University Health Centre and assistant professor at McGill University.The aim is to not only increase sensitivity, so there’s an earlier diagnosis of MS, but also ensure specificity, to reduce misdiagnosis. “It’s not an insignificant misdiagnosis rate; it’s thought to be as high as 20% in specialist MS symptoms,” he said.The new criteria include more specificity criteria to “help us really get to the matter of what is MS and what is not MS,” Dr. Thebault said.“The tree diagram of how you diagnose MS just has a lot more branches on it,” Dr. Thebault said.These tests “are my bread and butter,” Dr. Thebault said, adding that he performs them every day. “It really highlights the importance of a specialist and a centre, because you need to have access to these tests,” and an expert and radiologist familiar with these tests.Use of optic nerve as fifth dissemination in space topographyA diagnosis of MS relies on indications of disease dissemination in space and dissemination in time. To ensure that there has been dissemination in space, there needs to be proof of lesions in certain areas. Previously, there were only four affected areas where damage was considered indicative of MS. Now, the 2024 McDonald criteria suggests a lesion in the optic nerve can be used as evidence of MS. This can be detected through MRI or evoked potentials. Dr. Thebault noted that experts also need to know differential diagnoses of what would cause a lesion in an optic nerve. It can be subjective if bands are present or not, and can lead to misdiagnosis. The 2024 McDonald criteria also note that if lesions exist in four or five of the different topologies, then physicians can proceed to diagnose MS, even when there’s no proof of dissemination in time.Oligoclonal bands vs Kappa free light chainsOligoclonal bands seen in cerebral spinal fluid (CSF) is a long-used biomarker of MS, but identifying if these bands are present or not can be subjective, Dr. Thebault said. This can lead to missed diagnoses.The Kappa free light chain index is another test using CSF and is a measure of antibody synthesis and an indication of inflammation. It is now considered equivalent to the oligoclonal bands as a CSF-based biomarker suggesting identifying MS. The higher the Kappa free light chain index, the greater the specificity of an MS diagnosis. The test can be partly automated, where processing oligoclonal bands require experienced labs, explains a paper in Frontiers in Immunology. It takes a lab technician about half a day to produce oligoclonal bands, but much less time to measure Kappa free light chain index. It’s also cheaper and there is less variability in results depending on what assay is used. “The key thing here is it is much easier. It saves a huge amount of labour,” Dr. Thebault said. The inclusion of the Kappa free light chain index in the 2024 McDonald Criteria for the diagnosis of MS is discussed in a paper in Neurology and Therapy.While Kappa free light chains are used as diagnosis biomarker, they may also have utility as a prognostic marker, Dr. Thebault said.Central Vein Sign (CVS)Vessels, mainly veins and venules, are often present in MS plaques. The periventricular space around these veins can be a site of inflammation, leading to a lesion around the veins. With higher field MRI, these veins in MS plaques can be detected, known as the central vein sign. The presence of at least six central vein sign-positive lesions can be used as a biomarker for MS. This is known as the Select 6 rule. Detecting the central vein sign requires specific MRI techniques and sequences. The North American Imaging in Multiple Sclerosis Cooperative has a consensus statement in assessing central vein sign. The imaging magnet strength also matters, so 1.5 Tesla is the most common and can see it, but stronger magnets are better.A potential barrier to using the central venous sign is radiologist buy-in. “Not only do you have to convince a radiologist to add this extra sequence that takes about five minutes, then convince them to read these and count six, and that takes time as well,” Dr. Thebault.Other imaging tests that show dissemination in time is a gadolinium-enhancing lesion or a new T2-weighted lesion on a follow-up MRI scan.Paramagnetic Rim LesionsParamagnetic rim lesions are another pathological hallmark of MS that can be used in diagnosis. After the initial insult on the central nervous system in MS, the immune system does not leave, “it actually sets up shop,” Dr. Thebault explained. In many lesions, there is a “smouldering edge” of ongoing inflammation that can be seen using the same MRI sequences as used in detecting the central vein sign. While these paramagnetic rim lesions are seen less commonly in MS, they are highly specific when seen. Radiologically isolated syndrome is now considered MSAnother big change in the 2024 McDonald Criteria is expanding the definition of MS. Previously, evidence of MS on MRI in the absence of symptoms was designated as radiologically isolated syndrome (RIS). The new McDonald criteria allow RIS to be diagnosed as MS if:there are demyelinating white matter lesions on T2-weighted MRI images in two of the five disseminations in space locations, andan imaging or biological biomarker exists This diagnosis, in the absence of symptoms, means that a person can begin treatment without having to wait for symptoms. The criteria change follows what it usually done in practice. “I think this is great because we know that 30% of these people develop MS over ten years,” Dr. Thebault said. Some people may already have MS.Prognostic biomarkersIt would be helpful to patients and physicians if there was a biomarker that could shed light on the progression of the disease. Researchers are investigating a few candidate biomarkers for progression.Neurofilament light chainNeurofilament light chain (NfL) is a nonspecific biomarker that shows neuronal-axonal damage. There are now high sensitivity platforms that allow physicians to measure it in the blood, as serum neurofilament light chain (sNfL). It was previously measured primarily using CSF. Researchers now often include sNfL measures in clinical trials to measure response to therapy in MS. There is some suggestion it could be used to predict progression in MS. Dr. Thebault and colleagues published a study in 2022 suggesting that higher sNfL levels was associated with a higher rate of subsequent relapse in 58 Canadian and Italian MS patients. Dr. Thebault and other Canadian MS experts wrote a review of clinical applications of neurofilaments as biomarkers, published in Nature Reviews Neurology in 2024.A big limitation of using sNfL as a prognostic biomarker is that sNfL is not specific. Other comorbidities, even age and BMI may affect it, so any measure of sNFL needs to adjust for these factors. There are large datasets that better allow interpret these numbers, “but the clinical interpretation of them is not fantastic,” Dr. Thebault said. There are also interoperability differences between the different assay platforms. “It is a work in progress.” Glial Fibrillary Acidic ProteinGlial Fibrillary Acidic Protein (GFAP) shows damage in astrocytes and is being studied as a possible way to measure disease progression. For example, in a 2015 study, high GCAP levels in the CSF have been associated with a faster decline in ability as measured by the Expanded Disability Status Scale.A large study published in 2024 compared sNfL and GFAP as predictors of MS progression. Both markers could predict disease worsening, but “the real magic is when we combined the two markers togther,” Dr. Thebault said. Other groups have investigated GFAP as a way to monitor subclinical progression of MS. The 2024 revisions of the McDonald Criteria were published in October 2025 in the Lancet Neurology. Dr. Thebault spoke at the at the Canadian Neurological Sciences Federation annual congress, held in Ottawa in June.

How biomarkers are helping with MS diagnosis and prognosis

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