Unlocking the Mystery of Prodromal MS With a Key Biomarker

Damian McNamara

September 25, 2019

STOCKHOLM — Elevated serum levels of the neurofilament light chain biomarker could flag people who are in a prodromal phase of multiple sclerosis (MS), indicating before the first symptom that they will likely develop the demyelinating disease, new research indicates.

Compared to healthy controls, a group of people who developed MS had significantly elevated serum neurofilament light chain (sNfL) levels for a median of 1 year before and 1 year after symptom onset.

"Our results indicate that neurofilament light chain is a useful biomarker for disease activity around the time of the first MS symptoms. Further, they suggest that the disease processes in MS may start years before the first symptoms of the disease," principal investigator Kjetil L. Bjornevik, MD, PhD, research scientist in the Department of Nutrition at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, told Medscape Medical News.

The findings were presented here at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019, and simultaneously published online in JAMA Neurology.

Prodromal Phase

Previous research has demonstrated that many people already feature central nervous system lesions at the onset of MS. Other studies indicate that people with MS more frequently seek medical care in the 5 years before their first symptom compared with controls.

"This could be consistent with a presymptomatic or prodromal phase of the disease. However, these are indirect markers," Bjornevik said at the conference.

Even though MS "likely starts before patients experience their first symptom," little is known about this phase, he said.

To learn more, the researchers evaluated serum samples from 245 military personnel with MS in the US Department of Defense Serum Repository. They randomly selected 60 people with MS from this group and performed two different analyses with 30 people each. They also enrolled healthy controls matched for age, sex, race/ethnicity, and approximate date of sample collection in this nested, case-controlled study.

To determine if sNfL levels are elevated around the time of symptom onset, their first substudy compared a group with one sNfL measurement before and one after MS diagnosis. Compared with controls, the MS group had significantly elevated levels a median of 1 year before first symptom onset (P = .002) and a median 1 year after symptom onset (P < .001).

In addition, the researchers found a significant increase in sNfL levels in most patients from the pre-onset to the post-onset phase (P = .009). "In contrast to this, there was no significant difference between the first and second sample in controls," Bjornevik said.

"Serum NfL appears to be a sensitive marker to capture the first clinical event in MS."

In a second substudy, designed to detect elevated sNfL levels years before the first symptom, the investigators evaluated serum measures 2 to 5 years before and 5 or more years before diagnosis.

Compared to controls, sNfL levels were higher a median of 6 years and again a median of 1 year before symptom onset. The difference at 1 year was statistically significant (P < .001).

"The sNfL levels increased markedly between these two time points in MS patients," Bjornevik said. At the same time, levels did not differ significantly among controls.

These findings suggest, "sNfL elevation often precedes the clinical onset of MS by several years."

"Overall, the results indicate that MS may have a presymptomatic phase lasting several years and that neuroaxonal damage — as indicated by the elevated sNfL levels — may occur already during this phase," Bjornevik said.

The results of this early study need to be replicated, he added. "We are planning to conduct a larger study including more MS patients to better understand the presymptomatic phase of the disease."

"Interesting" Observation

"Serum NfL is a very promising marker, and works well on the group level," Bernhard Hemmer, MD, director of the Neurology Clinic and professor of neurology at Technical University Munich School of Medicine in Germany, told Medscape Medical News when asked to comment.

"We do not think now we can use it as a routine test for individual patients," added Hemmer, who is also president of ECTRIMS. "The other problem is it is very expensive, about 50 to 100 euros per test."

"They found that many years before the first clinical symptoms, [sNfL] was elevated and continued to elevate, so this was quite an interesting observation and study," Aksel Siva, MD, Department of Neurology at Istanbul University Cerrahpasa School of Medicine in Turkey, said during a Clinical Highlights session at ECTRIMS.

"We now know that a prodromal phase before the diagnosis of MS exists at least for a number of patients…and we have the sNfL marker that will be elevated before people develop the disease."

"This is an important concept that we should continue to [evaluate]," Siva added. 

An Association With Diabetes?

In a separate presentation at ECTRIMS, other researchers looked at sNfL, comorbidities, and patient outcomes in a large, cross-sectional study of people with MS.

"Most existing sNfL studies are conducted in homogenous clinical study populations," Kathryn Fitzgerald, ScD, assistant professor of neurology at Johns Hopkins School of Medicine in Baltimore, Maryland, said at the conference.

To get a more "real world" picture, she and colleagues compared 1969 participants in the multicenter MS Partners Advancing Technology and Health Solutions (MS PATHS) network with 130 healthy controls. The 483 people (or 25%) with elevated sNfL levels were more likely to have poorer cognitive function and diabetes compared with those who had normal sNfL assays.

Compared to the normal sNfL participants, the group with elevated levels had 10% slower walking speeds (95% confidence interval [CI], 6%-14%; P < .001). They also tested 7% slower on manual dexterity (95% CI, 5% - 10%; P < .001).

Similarly, the elevated biomarker cohort had lower processing speed scores (mean difference, –3.78; 95% CI, –4.84 to –2.70; P < .001).

Fitzgerald and colleagues also found patients with diabetes were more than twice as likely to have elevated sNfL levels (odds ratio, 2.24; 95% CI, 1.41 - 3.58; P = .0007).

The researchers found no notable differences by sex, age, race, or presence of hypertension, hyperlipidemia, or renal dysfunction. In addition, no significant relationship with body mass index emerged.

The research "supports the existing evidence that serum NfL is a promising candidate for measuring disease burden in people with MS." Fitzgerald added, "Follow-up studies are needed to assess if comorbidities modify longitudinal associations."

The National Institute of Neurologic Disorders and Stroke and the Swiss National Research Foundation provided funding for the MS prodromal study. Biogen supports the MS PATH network database. Bjornevik has disclosed no relevant financial relationships. Siva disclosed he received honoraria or consultant fees from Novartis, Sanofi-Genzyme, F. Hoffmann-La Roche, Biogen Idec, Gen Pharma, Bayer, Merck Serono, and Teva. Fitzgerald has disclosed no relevant financial relationships.

35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019. Abstracts 23 and 284. Presented September 11 and 13, 2019.

JAMA Neurol. Published online September 13, 2019. Abstract

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