Neurofilament Light Levels at First MS Event Can Predict Long-term Brain Atrophy

The levels of the protein neurofilament light chain (NfL) in the blood when a person experiences a first demyelinating event associated with multiple sclerosis (MS) can predict brain atrophy up to a decade later, a new study shows.

Titled “Association of Serum Neurofilament Light Levels With Long-term Brain Atrophy in Patients With a First Multiple Sclerosis Episode,” the study was published in JAMA Network Open. The study was sponsored by Biogen.

Clinically isolated syndrome, or CIS, is seen as the first clinical presentation of MS. CIS refers to a neurologic event characterized by inflammatory demyelination — the loss of myelin, the protective coating surrounding nerve fibers whose loss is a hallmark of MS — of the optic nerve, spinal cord, or neurons in the brain.

Currently, there are no biomarkers able to provide long-term prognostic information about the likely disease course for a person who presents with CIS. Identifying such markers could allow healthcare providers to give their patients more accurate diagnoses and inform decisions about treatment.

NfL is a protein found in neurons that gets released into body’s fluids when neurons become damaged. As such, NfL has been used as a marker of short-term neuronal damage. However, data is scarce on the association of NfL levels at a first CIS presentation with long-term disease outcomes.

In the new study, researchers at Biogen and the University of California, San Diego, investigated the prognostic utility of blood NfL levels using data from the clinical trial CHAMPS and its long-term extension CHAMPIONS (NCT00179478).

These trials evaluated Biogen’s Avonex, a formulation of interferon beta-1a, as a treatment for people presenting with CIS and brain MRI lesions suggestive of MS.

In total, 308 participants had blood NfL levels measured at their first study visit (baseline). Similar to the overall study population, the mean age of these patients was 33.2 years and 234 (76%) were women.

The NfL levels at the study’s start were significantly associated with the baseline number of actively inflamed brain lesions — that is, people with higher NfL levels were statistically more likely to have more lesions.

Using statistical models, the researchers determined whether clinical factors at baseline — including blood NfL levels — were significantly predictive of brain parenchymal fraction (BPF) at five or 10 years later. BPF is a measure of brain volume; a decrease in BPF suggests brain atrophy.

The results at five years showed that blood NfL levels were significantly predictive of change in BPF. The participants with the highest baseline NfL levels had significantly larger reductions in BPF after five years (minus 1.83% in BPF), relative to those with the lowest levels (minus 0.95%).

The total number of brain lesions at baseline also was significantly predictive of BPF change after five years.

The blood NfL levels also were significantly associated with BPF change after 10 years. Again, participants with the highest baseline NfL levels had significantly larger BPF reductions — now minus 3.54% — relative to those with the lowest levels, whose reductions now were minus 1.90%.

Brain lesions and other factors were not significantly predictive of BPF changes after 10 years, the results showed.

“Baseline serum neurofilament light levels at the time of the first demyelinating event were found to be associated with brain atrophy, as measured by BPF change over 5 and 10 years,” the researchers wrote.

“We speculate that the high serum neurofilament light levels reflect neuroaxonal damage [damage to neurons] associated with the inflammatory process,” they added.

Of note, after five years, six of the 45  participants (13.3%) in the group with the highest NfL levels and two of 52 participants (3.8%) in the lowest NfL levels group had an expanded disability status score (EDSS) of 3.5 or higher, indicating moderate disability. Although this trend suggests that NfL levels also may be predictive of disability progression, “the small numbers preclude statistical testing,” the researchers wrote.

Overall, the results “suggest that serum neurofilament light level may be an important component of a multidimensional measure to estimate prognosis and stratify risk of severe disease,” the team wrote.

The researchers stressed the importance of validating these results in further studies, and the need to define meaningful cut-off values to define “high” or “low” blood NfL levels. Assays able to measure NfL that can be easily implemented into clinical practice also are needed, they said.

Furthermore and “importantly, it remains to be demonstrated that lowering serum neurofilament light levels results in reduced disease progression in later years. If that were the case, serum neurofilament light could be used as a prognostic marker and a treatment-response marker,” they wrote.

“If validated in prospective studies, it could potentially be used alongside clinical and radiological assessments for prognosticating disease in routine clinical practice, thereby facilitating the selection of appropriate treatment and potentially leading to better outcomes in patients with MS,” the researchers concluded.