Biomarker in Blood Predicts Multiple Sclerosis Progression 1 to 2 Years in Advance

Summary: Researchers has found that elevated levels of NfL in the blood of multiple sclerosis (MS) patients could signal worsening disability within the next one to two years. This first-of-its-kind study pinpoints a crucial timeframe for potential interventions.

By analyzing data from nearly 1,900 patients over a decade, the team discovered that high NfL levels correlate with a significant risk of disability progression, with or without relapse.

These findings underscore the importance of NfL as an early biomarker for nerve damage and could pave the way for preemptive treatments in MS.

Key Facts:

1. Elevated neurofilament light chain (NfL) levels may predict MS disability progression 1-2 years in advance.
2. The study analyzed a 10-year data set from almost 1,900 MS patients, revealing NfL’s role in both relapsing and progressive forms of MS.
3. High NfL levels were linked to up to a 91% higher risk of disability worsening post-relapse and a 49% risk without relapse.

Source: UCSF

Multiple sclerosis patients whose blood tests reveal elevated NfL, a biomarker of nerve damage, could see worsening disability one to two years later, according to a new study spearheaded by researchers at UC San Francisco.  
 
The study is the first to quantify the timeframe preceding disability worsening in which injury to the central nervous system takes place, said co-first author Ahmed Abdelhak, MD, of the UCSF Department of Neurology and the Weill Institute for Neurosciences. 

Almost 1 million Americans suffer from MS. In advanced cases, patients may have limited mobility and experience spasticity, weakness, poor coordination and incontinence. However, recent advances suggest that more severe symptoms can be substantially delayed or even averted. 
 
“This rising of NfL up to two years before signs of disability worsening, represents the window when interventions may prevent worsening,” said Abdelhak.  
 
In the study, publishing in JAMA Neurology on Nov. 6, 2023, and co-led by University Hospital and University of Basel, in Switzerland, the researchers looked at the incidence of disability worsening, defined as six months or more of increased impairment reflected in a higher score on the Expanded Disability Status Scale.

They distinguished between disability worsening with relapse, which involves residual symptoms or the return of old ones following relapse, and gradual progression of symptoms without relapse.  
 
91% at elevated risk of developing disability worsening 
 
The researchers tracked data spanning a 10-year period from approximately 4,000 patient visits to UCSF, comprising the EPIC study, and from approximately 9,000 patient visits to multiple sites in Switzerland, comprising the SMSC study.

Together, the two studies included almost 1,900 patients. Among those, 570 patients were identified with disability that continued to worsen, of which the majority were independent of relapses. 
 
Elevated NfL levels were associated with up to a 91% higher risk of worsening disability with relapse approximately a year later, and up to a 49% higher risk of worsening disability without relapse nearly two years later, the researchers found.  
 
“We think that NfL elevation occurs earlier in disability worsening without relapse,” said Abdelhak. This different pattern may indicate “a more prolonged process that decreases in intensity in advance of increased impairment,” said co-senior author Ari Green, MD, medical director of the UCSF Multiple Sclerosis and Neuroinflammation Center.

“This aligns with recognition that death of nerve cells is a slow process that builds toward permanent disability and means that interventions to protect nerve cells might have time to also stop disability,” he said. 
 
“In addition to the groundbreaking findings on the temporal relationship between NfL increases and gradual disease progression in MS, the study supports the important role of NfL as an early marker of nerve damage,” said co-senior author Jens Kuhle, MD, PhD, who led the Swiss cohort and is head of the Multiple Sclerosis Center at University Hospital and University of Basel, Switzerland.

“Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging,” he said.  
 
Future investigation will look into therapies that can stop progression during this period of elevated NfL.  
 
Authors: Co-first author is Pascal Benkert, PhD, of University Hospital and University of Basel, Switzerland. Co-senior author is Jens Kuhle, MD, PhD, also of University Hospital and University of Basel, Switzerland. For other authors, please see the study. 

Funding: Westridge Foundation Grants from F. Hoffmann-La Roche, Fishman Family, grant 320030-160221 from the Swiss National Research Foundation, grant R35NS111644 from the NIH/NINDS, the Valhalla Foundation. The UCSF MS biorepository is supported by grant Si-2001- 375 35701 from the National MS Society. 

About this multiple sclerosis research news

Author: Suzanne Leigh
Source: UCSF
Contact: Suzanne Leigh – UCSF
Image: The image is credited to Neuroscience News

Original Research: Closed access.
“Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis” by Ahmed Abdelhak et al. JAMA Neurology

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Abstract

Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis

Importance  

Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting.

Objective  

To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW).

Design, Setting, and Participants  

This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate.

Exposure  

Association between NfL z scores and CDW.

Main Outcome Measures  

CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(−2) for 2 visits preceding event, CDW(−1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively.

Results  

A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(−1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(−2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(−1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years).

Conclusions and Relevance  

This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.