In serum samples drawn a median of 6 years before clinical onset of the disease, NfL levels were higher in people who eventually developed MS than in matched controls (median 16.7 pg/mL vs 15.2 pg/mL, P=0.04), reported Kjetil Bjornevik, MD, PhD, of Harvard T. H. Chan School of Public Health in Boston, at the ECTRIMS congress. The findings were published simultaneously in JAMA Neurology.
"MS may have a pre-symptomatic or prodromal phase lasting several years, and neuroaxonal damage may occur already during this phase," Bjornevik stated.
disease processes in MS likely start before patients experience their first symptoms, but little is known about this phase, such as how long it is and what happens during it, Bjornevik explained. At disease onset, for example, patients often have central nervous system lesions in different stages of evolution, indicating that subclinical demyelinating events may have occurred in the past.
Incidental white matter lesions observed in radiologically isolated syndrome can occur years before MS onset, he added, and MS patients often report clinical symptoms and disturbances to their general practitioner up to 10 years before their MS diagnosis. But these are indirect markers, Bjornevik noted: it's not clear whether they truly represent a prodromal phase of MS.
In this nested case-control study, Bjornevik and colleagues evaluated serum neurofilament light chain, a specific marker of neuroaxonal degeneration, as a potential indicator of a pre-symptomatic phase in MS.
They studied active-duty U.S. military personnel who had at least one serum sample stored in the Department of Defense Serum Repository, identifying 245 MS patients from 2010 and 2011 samples. The mean age of these patients was 27.5 at baseline and 76.7% were men. Serum NfL concentrations were measured using an ultrasensitive single-molecule array (Simoa) assay.
The researchers evaluated two groups of MS patients from this cohort. "In the first group, we randomly selected 30 MS patients who had one sample collected before MS onset, and one sample collected shortly after, with MS onset defined as the first symptoms of the disease," Bjornevik said. The group could help determine whether NfL was elevated around the time of first MS symptoms, he noted.
In the second group, they randomly selected 30 MS patients who had two pre-onset samples, one collected 2 to 5 years before diagnosis, and one collected more than 5 years before diagnosis. "The purpose of this group was to determine whether NfL was elevated years before the time of the first MS symptoms," Bjornevik explained.
In addition, the researchers selected one healthy control for each MS case, matched by age, sex, race and ethnicity, and approximate date of sample collection.
In the first group, serum NfL levels were significantly elevated at both time points -- a median of 1 year before MS onset and a median of 1 year after MS onset -- compared with matched controls. "The NfL levels increased markedly in MS cases around the time of MS onset, compared to the levels in the matched controls, and thus appeared to be a sensitive marker to capture the first clinical event in MS," Bjornevik noted.
In the second group, NfL levels were higher in both the first pre-symptomatic sample -- which was collected a median of 6 years (range 4 to 10 years) before first MS symptoms -- and in the second sample -- which was collected a median of 1 year before first symptoms -- compared with controls. This difference increased as the sample collection dates grew closer to the date of MS onset.
A within-person increase in pre-symptomatic NfL levels also was linked to higher MS risk, Bjornevik noted.
The study has several limitations: sample sizes were small and results largely reflect data about men; it's unknown whether the findings apply to women. While NfL is a marker of neuroaxonal damage, it is not specific to MS, and other factors like traumatic brain injury may have affected outcomes. Because the sample sizes were small, the researchers could not evaluate cutoffs in serum NfL levels that may point to the start of an MS prodromal phase.
The study was funded by the Swiss National Research Foundation and the National Institute of Neurologic Disorders and Stroke/NIH.
Researchers disclosed relevant relationships with Novartis, Merck Serono,Verily Life Sciences, Genzyme, the Swiss MS Society, the Swiss National Research Foundation, Bayer, Biogen, Protagen AG, Roche, and Teva.