Observational study identifies blood proteins indicating multiple sclerosis risk years before diagnosis — Evidence Review
Published in Nature Medicine, by researchers from UC San Francisco
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Table of Contents
Researchers from UC San Francisco have identified blood protein changes that signal multiple sclerosis (MS)–related brain damage years before symptoms emerge. These findings are broadly supported by other recent studies, which highlight the value and challenges of blood biomarkers for early MS detection and monitoring.
- Several related studies confirm that blood and cerebrospinal fluid proteins can provide early indicators of MS risk, disease activity, and progression, but emphasize the complexity of identifying reliable and specific markers due to overlapping profiles with other neurological conditions and confounding factors such as age and body mass index 1 2 4.
- The new study’s timeline—showing myelin injury preceding axonal damage by years—aligns with longitudinal biomarker research indicating that neurofilament light chain (NfL) and other proteins rise before clinical symptoms, and that combinations of multiple proteins improve prediction of disease activity and disability 3 4 5.
- There is growing consensus that panels of biomarkers, rather than single proteins, are needed for accurate early MS diagnosis and prognosis, a view echoed in recent systematic reviews and proteomic studies that identify numerous novel protein candidates and call for further clinical validation 3 4 7.
Study Overview and Key Findings
Early diagnosis and intervention are critical in multiple sclerosis, a disease often well underway by the time symptoms prompt clinical attention. This new study leverages a unique resource—archived blood samples from military service members—to analyze thousands of proteins and reconstruct the earliest immune and neurological changes leading to MS. Unlike previous research, which often relied on symptomatic patients or imaging findings, this work provides a direct molecular timeline of MS onset and progression, potentially paving the way for pre-symptomatic diagnosis and prevention strategies.
| Property | Value |
|---|---|
| Study Year | 2025 |
| Organization | UC San Francisco |
| Journal Name | Nature Medicine |
| Authors | Ahmed Abdelhak, Gabriel Cerono, Fahime Sheikhzadeh, Adil Harroud, Kiarra Ning, Colin R. Zamecnik, Gavin M. Sowa, John Boscardin, Christian Cordano, Asritha Tubati, Camille Fouassier, Eric D. Chow, Refujia Gomez, Adam Santaniello, Kelsey C. Zorn, Jill A. Hollenbach, Jorge R. Oksenberg, Bruce A. C. Cree, Stephen L. Hauser, Jonah R. Chan, Sergio E. Baranzini, Mitchell T. Wallin, Michael R. Wilson, Ari J. Green |
| Population | People with multiple sclerosis |
| Sample Size | 134 people |
| Methods | Observational Study |
| Outcome | Blood protein levels indicating risk of MS |
| Results | Identified 50 proteins signaling increased MS risk years before diagnosis |
Literature Review: Related Studies
To contextualize these findings, we searched the Consensus research paper database (over 200 million papers) for relevant literature. The following search queries were used:
Below, we organize key findings from the literature into central topics:
| Topic | Key Findings |
|---|---|
| How early can blood or fluid biomarkers predict MS onset or activity? | - Blood and cerebrospinal fluid (CSF) proteins such as neurofilament light chain (NfL), MOG, and various immune-related markers can predict MS risk and activity before symptoms arise 1 3 4 5. - Combinations of multiple biomarkers improve diagnostic accuracy and prediction of disease progression compared to single markers 1 3 4. |
| What is the role of myelin and axonal injury in early MS pathology? | - Evidence shows myelin damage often precedes axonal injury, with markers like MOG rising before NfL in preclinical MS 3 4 12. - Early microstructural brain changes, including non-lesional damage, can be detected using diffusion tensor imaging and advanced MRI, sometimes before focal lesions or symptoms appear 12 14. |
| Which proteins or immune pathways are linked to MS risk or progression? | - Multiple immune-related proteins (e.g., IL-3, SLAMF7, TYMP, FCRL3) and signaling pathways (e.g., mTOR, HERV-W) have been identified as candidate biomarkers and potential drug targets for MS 6 7 8 10. - Panels of novel plasma and brain proteins, including those involved in immune cell recruitment and myelin integrity, are associated with MS susceptibility and disability worsening 7 9. |
| How can biomarkers improve MS diagnosis, prognosis, and treatment? | - Biomarkers can aid in early diagnosis, monitor disease activity, predict disability progression, and guide personalized treatment strategies, but clinical translation is limited by confounding factors and lack of specificity 2 4 5. - Imaging and fluid biomarkers are increasingly being integrated for comprehensive disease monitoring, with ongoing research into multi-marker panels and advanced neuroimaging 2 4 11 15. |
How early can blood or fluid biomarkers predict MS onset or activity?
A growing body of evidence supports the use of fluid biomarkers—including proteins in blood and cerebrospinal fluid—for early detection of MS risk and disease activity, sometimes years before clinical symptoms arise. The new study's identification of myelin and axonal damage years before diagnosis is consistent with these findings, though it stands out for reconstructing a detailed molecular timeline.
- Blood and CSF proteins such as NfL and MOG can be elevated well before symptom onset, providing early warning of MS risk 1 3 4 5.
- Combining multiple protein biomarkers generally improves prediction of MS onset and progression compared to single markers 1 3 4.
- Confounding factors and overlap with other neurological conditions remain challenges for specificity and clinical utility 4 5.
- The new study adds unique data by demonstrating a sequential pattern of biomarker changes, reinforcing the value of longitudinal sampling 3 4.
What is the role of myelin and axonal injury in early MS pathology?
The sequence in which myelin and axonal injury occur is central to understanding MS pathogenesis. The new study's finding—that myelin damage precedes axonal injury by about a year—aligns with recent imaging and biomarker research.
- Myelin injury (as indicated by MOG) appears before axonal injury (NfL) in the preclinical phase of MS 3 12.
- Diffusion tensor imaging and advanced MRI often detect microstructural changes, such as cerebellar damage and reduced brain integrity, prior to the appearance of clinical symptoms or macroscopic lesions 12 14 15.
- Some imaging markers associated with MS risk and progression are detectable in normal-appearing white matter, suggesting that hidden brain damage is an early feature 12 14.
- There is agreement that early intervention targeting myelin protection may be beneficial, but more research is needed to translate these findings into therapies 3 4 12.
Which proteins or immune pathways are linked to MS risk or progression?
Identification of specific proteins and immune pathways associated with MS is an active area of research, with the new study highlighting IL-3 as a key early marker. Recent literature expands this list to a broad array of candidates.
- Multiple immune-related proteins—including IL-3, SLAMF7, TYMP, FCRL3, and HERV-W—have been implicated as biomarkers and potential therapeutic targets 6 7 8 10.
- Novel proteins identified through proteomics and genetic studies are associated with MS susceptibility, disease progression, and disability 7 9.
- The involvement of mTOR signaling and other immune pathways suggests potential for targeted prevention strategies 8.
- There is significant heterogeneity in protein expression profiles between individuals, highlighting the need for personalized approaches 7 9.
How can biomarkers improve MS diagnosis, prognosis, and treatment?
Biomarkers hold considerable promise for improving MS care by enabling earlier diagnosis and more precise prognostication. However, the literature also highlights significant limitations and the need for further clinical validation.
- Biomarkers can help to predict disability progression, monitor disease activity, and assess treatment response, supporting personalized treatment decisions 2 4 5.
- Integration of fluid and imaging biomarkers can improve diagnostic accuracy and disease monitoring, especially when combined in panels 2 4 11 15.
- Limitations include confounding by factors like age and BMI, lack of specificity, and the need for multi-marker strategies 4 5.
- The new study's approach—profiling a broad panel of blood proteins before clinical onset—exemplifies the direction of current biomarker research 3 4 7.
Future Research Questions
Despite advances in early detection of MS-related brain damage and the identification of promising biomarkers, important questions remain. Further research is needed to validate these findings in larger and more diverse populations, determine the clinical utility of multi-marker panels, and explore new therapeutic opportunities.
| Research Question | Relevance |
|---|---|
| How accurate are multi-protein panel blood tests for predicting MS in asymptomatic individuals? | Understanding predictive accuracy in real-world populations is essential for clinical adoption and may address current limitations in specificity and sensitivity seen with single biomarkers 1 3 4. |
| Can early immune biomarker changes be used to guide preventive therapies in MS? | If immune changes are detectable years before symptoms, there is potential to develop interventions that prevent or delay onset; however, this approach requires rigorous clinical testing and ethical consideration 3 4 8. |
| Which combination of fluid and imaging biomarkers provides the best prediction of MS progression? | Combining modalities may overcome the limitations of each approach alone, but optimal panels and protocols remain to be established through comparative studies and validation 4 11 15. |
| What are the main biological mechanisms driving pre-symptomatic myelin injury in MS? | Elucidating the mechanisms that trigger myelin damage before symptoms could identify new therapeutic targets and inform prevention strategies 3 7 9. |
| How do genetic and environmental factors influence the early biomarker profile in MS? | Variability in biomarker expression may be shaped by genetic susceptibility and environment, affecting both risk and response to interventions; understanding these influences will be key for personalized approaches 7 8 9. |