Research published on October 20, 2025, in a top medical journal has drawn attention to the fact that multiple sclerosis (MS) develops in the brain for years before the first clear symptoms appear. It involves a precisely mapped sequence of events that begins with subtle but measurable damage to the myelin sheath, and then progresses to the nerve fibers themselves. This finding, supported by a large number of blood samples collected over an extended period, is changing the way we think about early recognition and potential prevention of the disease.

Why the “silent start” of multiple sclerosis is crucial for diagnosis and treatment

For decades, doctors have known that MS is not a sudden illness. When a patient first seeks help for tingling, double vision, balance problems, or sudden weakness, there are often years of unrecognized immune activity behind them. The new research has systematically reconstructed this early period: first, traces of myelin damage are recorded, then, after a time lag, signs of axonal damage. This “biological clock” of MS – first myelin, then the nerve fiber – creates the possibility of approaching the disease preventatively, rather than just reactively after the first attacks.

From a clinical standpoint, recognizing these hidden phases has immediate implications. Early intervention with disease-modifying therapies is already linked to better long-term outcomes. If therapies could be initiated while only biochemical signals are present, we could potentially delay, mitigate, or even prevent the first clinical episodes.

What the proteins in the blood revealed: “fingerprints” of damage and the orchestration of the immune reaction

A key tool in the new paper was proteomic analysis – measuring thousands of proteins in the blood over time. Using samples collected as part of a large military repository, researchers tracked changes in more than 5,000 protein markers. The earliest signal that stood out was a rise in the level of the protein MOG (myelin oligodendrocyte glycoprotein), which is considered an indicator of myelin damage. This “myelin signal” appeared, on average, seven years before a formal diagnosis. The next phase – approximately one year after the MOG spike – records neurofilament light chain (NfL), a protein that rises in the blood when there is damage to axons, the very “wires” of the nervous system.

Such a time lag between the two types of damage – first the insulation (myelin), then the conductor (axon) – confirms that the disease develops gradually and that there is a period during which the central nervous system is under attack, but without obvious symptoms. At the same time, elevated levels of specific cytokines that coordinate the immune response also appear in the blood. Among them, IL-3 stood out, a pro-inflammatory signal known for recruiting immune cells to the brain and spinal cord, where they then attack myelin and nerve cells.

The prodromal phase of MS: what life looks like before the first symptoms

The concept of a prodrome – a period in which the disease is already leaving biological traces, but without recognizable symptoms – is also becoming increasingly important in MS. Retrospective analyses suggest that people who later develop MS more often report non-specific complaints for years before diagnosis: frequent fatigue, episodes of mild dizziness, transient visual or concentration disturbances, and even unexplained pain. These signs alone are not sufficient for a diagnosis, but in combination with blood biomarkers, they could form an “early signature” of the disease that deserves neurological attention.

This is precisely why there is increasing talk in the literature about screening susceptible populations, for example, those with a family history of MS, people who have had certain viral infections linked to later risk, or young adults with an isolated neurological event (clinically isolated syndrome). In such groups, monitoring levels of MOG, NfL, and selected cytokines can offer an early window into the processes unfolding in the background.

What MOG and NfL tell us: the difference between demyelination and axonal injury

MOG is an integral part of the myelin sheath created by oligodendrocytes. When the immune system attacks myelin, fragments of myelin and associated proteins can enter the bloodstream, where they can be quantified using modern methods. A rise in MOG is, therefore, read as a signal of demyelination. In contrast, NfL is a structural component of the neuron's axon; an elevated level in the serum reflects axonal damage. In MS, these two processes often occur together, but the new research shows that demyelination may be the first event, with axonal damage following after a time lag.

This sequence is not just academically important. In clinical decision-making, it could help in choosing the right moment to intensify therapy, in monitoring the effectiveness of drugs, and in planning follow-up brain scans. If laboratory data reveal a rise in MOG with stable NfL levels and no new lesions on an MRI, the doctor can conclude that a process is underway that has not yet led to widespread axonal damage – and thus gain a crucial window of opportunity for intervention.

IL-3 and the early immune signature: who is “inviting” the cells into the brain

Among the many cytokines the authors tracked, interleukin-3 (IL-3) stood out as one of the most prominent. IL-3 acts as a signal to convene various immune cells, including monocytes and mast cells, and can amplify the inflammatory response in tissue. In the context of MS, an early rise in IL-3 suggests that the system is activating and being “organizationally” directed towards the central nervous system. Simply put, IL-3 is the megaphone calling forces to the site of future damage.

It is important to emphasize that this is not about one isolated marker, but a set of about 50 proteins whose patterns together are associated with the later development of the disease. The authors selected the 21 most informative biomarkers and filed a patent for the development of a blood test that would combine these signals into a diagnostic algorithm. Such a test could enable standardized and scalable risk recognition in the general population or targeted groups.

What this means for MRI and current diagnostic criteria

The diagnosis of MS today is based on a combination of the clinical picture, magnetic resonance imaging (MRI), and cerebrospinal fluid analysis, using internationally accepted criteria that were last revised in 2024. These criteria have significantly accelerated the confirmation of diagnosis after the first symptoms and facilitated the early use of therapy. However, the criteria are designed for the moment when symptoms already exist. The introduction of reliable blood markers could complement this approach – bridging the gap between the biological and clinical onset of the disease.

In practice, this could mean that a person with elevated MOG and NfL, along with certain cytokine signatures, would enter a protocol of more frequent MRI monitoring (e.g., every six months) and biochemical monitoring, in order to detect the first changes that meet the criteria for treatment. This reduces the risk of a “lost year” between the biological and clinical onset of the disease.

The great epidemiological puzzle: viruses, environment, genetics

In the last decade, the link between Epstein-Barr virus (EBV) infection and the risk of developing MS has been particularly strongly confirmed. Longitudinal analyses on millions of samples from young adults have shown that the risk of MS after seroconversion to EBV is many times higher. These findings take on a new dimension in light of proteomic signals: it is possible that the virus triggers an abnormal immune response that smolders for years, and only now are we learning to recognize it in the blood.

Alongside EBV, genetic factors (primarily variants within the HLA system), vitamin D, smoking, obesity in adolescence, and geographical differences in sun exposure also play an important role. New biomarkers could combine these factors into a unified risk score used to assess whose blood would “sound the alarm” years before symptoms.

What tomorrow's potential blood test looks like

In the laboratory, analyzing several thousand proteins requires advanced platforms; in practice, however, a clinical test must be robust, standardized, and accessible. Selecting the 21 most useful proteins is a step towards such a test. Imagine a panel that automatically measures MOG, NfL, and selected cytokines (including IL-3), and a computational model generates a single score ranging from low to high risk. This result, along with age, sex, family history, and any MRI findings, would guide decisions about the frequency of monitoring and the timing of therapy initiation.

It is important to keep in mind that NfL is not specific exclusively to MS: elevated levels can be seen in various neurological injuries (trauma, other inflammatory and neurodegenerative diseases). Therefore, it is interpreted in context, along with the clinical picture and other findings. Combined panels, as suggested by the new research, mitigate this problem because they rely on patterns, rather than individual values.

Early MS in practice: who to monitor and how

At the healthcare system level, early biological signals can be best utilized in targeted surveillance. For example, people who had mononucleosis in late childhood or adolescence, along with the presence of a certain genetic susceptibility, could be candidates for periodic biomarker testing. The same applies to individuals with clinically isolated syndrome (CIS), where a blood signature of inflammation and damage can help predict who will progress to MS and when.

For patients themselves, understanding that “silence” does not mean the absence of disease activity can change their relationship with self-monitoring and regular check-ups. Education about early, subtle signs – such as transient sensory changes, unexplained fatigue, or visual disturbances – gains new value when paired with objective laboratory measurements.

What's new in therapy and how biomarkers help in selection

The range of disease-modifying drugs today is broad and covers various mechanisms of action: from drugs that reduce the migration of lymphocytes into the central nervous system, to selective B-cell depleters, to oral preparations with an immunomodulatory effect. Biomarkers like NfL have already found a place as monitors of disease activity and therapeutic response: if the NfL value drops and remains low after introducing therapy, it is a good sign that the inflammatory activity is under control.

Introducing MOG and specific cytokine signatures into routine practice could further refine decisions – for example, escalating therapy more quickly when a rise in the “myelin signal” is seen, without waiting for a clinical relapse episode or MRI activity. Such an approach, focused on preventing damage instead of treating consequences, could reduce long-term disability and improve quality of life.

Children, adolescents, and women: special groups needing early attention

Although MS most commonly occurs in young adults, pediatric MS and MS in adolescents present additional challenges. In these age groups, even a short-term delay in diagnosis can have a greater developmental impact. Biomarkers that can be monitored in the blood, being minimally invasive and repeatable, are particularly valuable for young people. Similarly, women – who are more frequently affected than men – have specific life phases (pregnancy, postpartum period) where precise therapy titration and biomarker monitoring are of utmost importance.

MRI and blood “hand in hand”: how to coordinate imaging and laboratory

In clinical practice, there is no substitute for high-quality MRI scans of the brain and spinal cord. However, blood markers can fill the gaps between scans. A standard monitoring plan might include a baseline MRI scan, a follow-up in 6–12 months, and additional scans as clinically needed, while NfL, MOG, and cytokines are tested at shorter intervals (e.g., every 3 months). A rise in biomarkers would be a signal for an earlier MRI or a therapy adjustment.

Standardization and reference values: a stumbling block and an opportunity

For biomarkers to become a real clinical currency, we need age-specific reference ranges, an understanding of the impact of comorbidities, and clearly defined thresholds that predict clinical events. In this context, guidelines for the use of NfL already exist, but multi-parameter panels will require additional validation in international cohorts and inter-laboratory harmonization of methods.

Digital monitoring and personalized medicine

It makes sense to combine biological signals with digital phenotyping – data from smart devices (gait, fine motor skills, balance), cognitive tests on smartphones, and secure platforms for symptom tracking. Machine learning algorithms can use such multidimensional data, along with blood proteins, for personalized prognoses and recommendations.

What the reader can do: get informed and ask the right questions

If there is MS in your family or you have had mononucleosis in the past, it is worth talking to your doctor about rational biomarker monitoring. This does not mean getting tested blindly, but thoughtfully and with a clear purpose. In practice, steps may include a thorough neurological assessment, an MRI if indicated, and periodic assessment of MOG and NfL in a laboratory that has validated methods for these measures.

Resources for information

For basic concepts, review our thematic guide on multiple sclerosis and our section on biomarkers. There you will find descriptions of medications, explanations of MRI findings, and answers to questions that patients most frequently ask their neurologists.

Note on the date

This text was prepared taking into account today's date, October 21, 2025, and the latest data available up to that day. As scientific insights into MS are rapidly evolving, we recommend regularly following updates in our articles and consulting with your physician.