Silent Progression, Silent Signal: Rethinking Neurofilament Light as a Marker of Treatment Response in Progressive MS

Neurofilament light chain (NfL) in blood has been hailed as the Fitbit of axons—spiking when inflammatory damage erupts and dipping when treatments succeed. But does that same signal keep pace with the slower, smoldering decline that haunts people with progressive multiple sclerosis (MS)? A new post-hoc study of the phase-3 ASCEND trial says not so fast.

1. Why This Question Matters
For relapsing-remitting MS, dozens of studies have shown that serum NfL (sNfL) mirrors new MRI lesions, relapses, and even early treatment response. Regulators now encourage its use as an exploratory endpoint in drug development. Yet patients with secondary progressive MS (SPMS) often accumulate disability without obvious attacks or enhancing lesions. Clinicians need a blood test that tells them whether a therapy—such as the anti-integrin antibody natalizumab—is really slowing this “silent” progression.

2. How the Researchers Set Up a “Quiet” Experiment
Gafson and colleagues mined ASCEND, a double-blind natalizumab–placebo trial that followed 751 SPMS participants for 96 weeks. To isolate progression uncoupled from acute inflammation, they excluded anyone with relapses or new MRI activity at baseline and throughout follow-up, shrinking the cohort to 317 (214 on natalizumab, 103 on placebo). Disability was tracked by:

Expanded Disability Status Scale (EDSS)

Timed 25-Foot Walk (T25FW)

9-Hole Peg Test (9HPT)

Blood was drawn at baseline, week 48, and week 96 for ultrasensitive sNfL measurements.

3. The Headline Result—A Biomarker That Stood Still
Across 24 partial-correlation tests, 22 showed no link between percentage change in sNfL and either current or future changes in EDSS, T25FW, or 9HPT. The two “significant” findings went in opposite directions and likely reflected statistical noise. Logistic models told the same story: every 10 % rise in sNfL failed to predict confirmed disability progression, regardless of time window or treatment arm.

4. Why Didn’t sNfL Budge with Worsening Disability?
The authors propose several, mutually compatible explanations:

Different Biology. Progressive MS may hinge more on failed remyelination, chronic active (“smoldering”) lesions, and astroglial scarring than on fresh axonal transection that dumps NfL into blood.

Slow Burn vs. Fast Spike. sNfL has a short half-life; a gentle but relentless trickle of axonal loss may never cross the assay’s dynamic threshold.

Sparse Sampling. Three blood draws over 96 weeks could miss subtle oscillations.

These caveats align with newer longitudinal studies showing that baseline sNfL can forecast long-term outcomes in mixed progressive cohorts, but its short-term dynamics still correlate best with active inflammation.

5. What This Means for Treatment Response Studies
For anti-inflammatory drugs: sNfL remains a sensitive pharmacodynamic marker—drop-offs typically signal reduced lesion formation.

For neuroprotective or repair-promoting agents: relying solely on sNfL could under-detect benefit. Trials aiming to halt progression independent of relapse activity may need combinatorial biomarker panels—for example, pairing sNfL with MRI metrics of slowly expanding lesions or glial PET imaging.

6. Clinical Take-Home
If you’re caring for a 50-year-old woman with SPMS who hasn’t relapsed in years, a “normal” sNfL result should not reassure you that her disease is stable. Conversely, a modest uptick doesn’t automatically spell impending wheelchair use. Until we have broader, progression-specific biomarkers, functional testing and high-resolution imaging remain indispensable.

7. The Bigger Picture—Where Research Is Headed
Recent reviews call for high-frequency sampling, age-adjusted reference ranges, and head-to-head comparisons with other axonal proteins (e.g., GFAP, UCH-L1). Multi-omic efforts are already underway to integrate plasma proteomics, retinal OCT, and advanced MRI into a single “progression score” for individualized monitoring.

8. Bottom Line
The ASCEND post-hoc analysis delivers a sobering but clarifying message: serum NfL is a superb barometer of inflammatory injury, but a poor speedometer for the slow crawl of non-inflammatory progression in SPMS. Future trials—and everyday practice—will need to look beyond a single biomarker if we hope to measure what truly matters to patients: staying independent in the face of silent decline.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Gafson, A. R., Jiang, X., Shen, C., Kapoor, R., Zetterberg, H., Fox, R. J., & Belachew, S. (2022). Serum neurofilament light and multiple sclerosis progression independent of acute inflammation. JAMA Network Open, 5(2), e2147588-e2147588.