Summary: Researchers have traced the earliest stages of multiple sclerosis (MS), finding that the immune system begins to damage the brain years before clinical diagnosis. By profiling more than 5,000 proteins in blood samples, the team detected molecular signs of myelin damage—the insulating sheath that surrounds nerve fibers—well before symptoms appear.
Key biomarkers, including IL-3 and myelin oligodendrocyte glycoprotein (MOG), indicate a two-step process: an early assault on myelin followed by later injury to the nerve fibers themselves. These findings point toward the possibility of an early blood-based diagnostic test and raise the prospect of preventive interventions.
Key Facts:
- Early detection: Elevated MOG levels suggest myelin damage can be detected up to seven years before MS is diagnosed.
- Immune activation marker: IL-3 is prominent in the presymptomatic stage and is linked with recruitment of immune cells that drive early inflammation in the central nervous system.
- Potential test panel: The researchers identified roughly 50 proteins associated with future disease risk and prioritized 21 proteins for a proposed predictive blood test.
Source: UCSF
Overview: When people first seek care for symptoms that lead to an MS diagnosis, the disease process has often been active for years. Until recently, the sequence of biological events leading to symptomatic disease—and which central nervous system components are affected first—remained unclear.
Using high-throughput proteomics, researchers at the University of California, San Francisco analyzed thousands of proteins in archived blood samples to reconstruct the biological timeline that culminates in MS. Their analysis reveals a clear pattern: myelin injury appears long before symptoms and before measurable damage to axons, the nerve cell extensions responsible for transmitting signals.
The study measured both the debris released by damaged brain tissue and the circulating immune signals that direct inflammatory responses. By tracking these molecular changes in people who later developed MS, the team assembled a timeline showing the earliest detectable biologic events associated with the disease.
In practical terms, the data suggest a staged pathology: an initial phase characterized by myelin injury, detectable as a rise in MOG, followed about a year later by signs of axonal damage, reflected by increasing neurofilament light chain levels. During the early intervening period, immune-signaling proteins such as interleukin-3 (IL-3) are elevated and likely contribute to recruiting immune cells into the brain and spinal cord.
“These results create important opportunities for diagnosing, monitoring, and potentially treating MS earlier in its course,” said Ahmed Abdelhak, MD, assistant professor of Neurology at UCSF and the study’s first and co-lead author. The study was published in Nature Medicine and provides molecular evidence that disease processes start years before symptoms prompt clinical attention.
Samples came from the U.S. Department of Defense Serum Repository, a unique resource of blood specimens collected from service members at enlistment and stored for decades. The researchers examined samples from 134 individuals who went on to develop MS, comparing proteomic profiles from multiple time points before and after diagnosis with matched controls.
Results showed a distinct rise in MOG approximately seven years prior to clinical diagnosis, signaling early myelin damage. About one year after the MOG rise, neurofilament light chain levels increased, marking a transition to measurable axonal injury. Concurrently, IL-3 and several related immune mediators rose in the blood, suggesting active immune orchestration during the presymptomatic phase.
Across the study, roughly 50 proteins were associated with future MS development. The research team has applied for a patent covering a diagnostic approach based on the top 21 candidate proteins, pending further validation in independent cohorts.
Ari Green, MD, chief of Neuroimmunology and Glial Biology at UCSF and senior author on the paper, emphasized the implications: identifying disease activity before clinical onset raises the possibility of preventive strategies or early interventions designed to limit irreversible injury.
Authors: Other UCSF contributors include Gabriel Cerono, MD; Kiarra Ning; John Boscardin, PhD; the UCSF ORIGINS Study; Christian Cordano, MD, PhD; Asritha Tubati; Camille Fouassier; Eric D. Chow, PhD; Refujia Gomez; Adam Santaniello; Kelsey C. Zorn, MHS; Jill A. Hollenbach, PhD, MPH; Jorge R. Oksenberg, PhD; Bruce A.C. Cree, MD, PhD, MAS; Stephen L. Hauser, MD; Jonah R. Chan, PhD; Sergio E. Baranzini, PhD; Michael R. Wilson, MD; and Ari J. Green, MD. For the full author list and details, refer to the published paper.
Funding: The study received support from multiple sources, including the U.S. Department of Defense and the National Institutes of Health, as well as private foundations and donor support. Specific grant numbers and disclosures are reported in the paper.
Key Questions Answered:
A: The study indicates that immune activity against myelin can be detected up to seven years before clinical symptoms or diagnosis, marking a much earlier biological onset than previously appreciated.
A: By analyzing archived blood samples collected from military personnel years before their diagnoses, researchers identified characteristic protein patterns—early rises in MOG and IL-3 followed later by neurofilament light chain—that signal progressive tissue injury.
A: These findings could transform early diagnosis and prevention strategies, enabling identification of at-risk individuals and intervention before irreversible nerve damage occurs, subject to validation in further studies.
About this multiple sclerosis and neurology research news
Author: Laura Kurtzman
Source: UCSF
Contact: Laura Kurtzman – UCSF
Image: The image is credited to Neuroscience News
Original Research: “Myelin injury precedes axonal injury and symptomatic onset in multiple sclerosis” by Ahmed Abdelhak et al., published in Nature Medicine. The full paper contains detailed methods, results, and author disclosures.
Abstract
Myelin injury precedes axonal injury and symptomatic onset in multiple sclerosis
The biological onset of multiple sclerosis is not well defined. Using high-throughput proteomic discovery and archived samples from individuals who were presymptomatic at the time of collection, the investigators defined a biological onset and characterized early mechanisms. Evidence of myelin injury appeared approximately seven years before symptomatic onset and preceded detectable axonal injury by about one year. Astrocyte involvement emerged closer to clinical onset. Serum proteome changes implicate interleukin-3 and NF-kappa-B pathways during the presymptomatic stage. Individuals with a previously reported autoantibody signature displayed greater immune cell activation. The authors propose a protein biomarker panel to distinguish presymptomatic individuals at risk for MS from healthy controls, pending further validation. These findings advance understanding of MS pathophysiology and may support earlier detection in high-risk populations.