Patients with multiple sclerosis (MS) whose blood tests reveal elevated neurofilament light chain (NfL), a biomarker of nerve damage, are at risk of experiencing disability worsening one to two years later, according to a new study spearheaded by UCSF researchers.
The study is the first to quantify the time frame preceding disability progression in which injury to the central nervous system takes place, according to co-first author Ahmed Abdelhak, MD, of the UCSF Department of Neurology and Weill Institute for Neurosciences. “This elevation of NfL up to two years before signs of disability worsening represents the window when interventions may prevent it,” he said.
In the study, co-led by University Hospital Basel and the University of Basel in Switzerland, researchers looked at the incidence of confirmed disability worsening (CDW), defined as six months or more of increased impairment reflected in a higher score on the Expanded Disability Status Scale. They distinguished between CDW with relapse, which involves residual symptoms or the return of old ones following relapse, and gradual progression of symptoms without relapse.
Elevated NfL associated with up to 91% risk of disability worsening
The researchers tracked data from approximately 4,000 patient visits to UCSF over a 10-year period, comprising the EPIC study, and from approximately 9,000 patient visits to multiple sites in Switzerland, comprising the Swiss MS Cohort study. Together, the two studies included almost 1,900 patients. Among those, 570 patients were identified with CDW, with the majority of the worsening occurring independent of relapses.
Elevated NfL levels were associated with up to a 91% higher risk of CDW with relapse approximately one year later and up to a 49% higher risk of CDW without relapse nearly two years later, the researchers found.
“We think that NfL elevation occurs earlier in disability worsening without relapse,” Abdelhak said. This different pattern may indicate “a more prolonged process that decreases in intensity in advance of increased impairment,” said co-senior author Ari J. Green, MD, medical director of the UCSF Multiple Sclerosis and Neuroinflammation Center and chief of the Division of Neuroimmunology and Glial Biology. “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 stop disability.”
“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, head of the Multiple Sclerosis Center at University Hospital Basel and the University of Basel. “Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging.”
Future investigations will explore therapies that can stop progression during this period of elevated serum NfL.
Laying the groundwork for discovery
This study builds on the team’s previous work. In 2017, Green and other UCSF researchers published the results of the ReBUILD clinical trial, the first randomized controlled study to show the efficacy of a remyelinating drug, clemastine, for treating chronic demyelinating injury in MS.
A 2022 study showed that clemastine reduced blood NfL in patients with MS, suggesting that remyelination is associated with neuroprotection. “This was the first strong evidence that remyelination actually protects axons in people. Protecting axons is a holy grail for neuroprotection in MS,” Green said.
Ongoing research and remyelination clinical trials
Green recently co-led a new mouse study that found demyelination to be associated with an increase in serum NfL and remyelination associated with a reduction. This provides a translational framework for understanding neuroaxonal injury in demyelinating conditions.
Four remyelination clinical trials are underway at UCSF:
Assessment of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis (ReCOVER)
Bazedoxifene Acetate as a Remyelinating Agent in Multiple Sclerosis
Through these trials, Green and his team are working toward providing personalized treatment for patients with MS. “A deeply detailed, multimodal approach is the best way to track individual patients and will give us the greatest capacity to intervene in a timely manner,” he said. “We strongly believe we are at the beginning of an age of therapies that can achieve brain repair.”
Neurology and neurosurgery research and treatment take place within the UCSF Weill Institute for Neurosciences.
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