Raised Serum NfL Levels May Indicate Chronic Active Lesions

Raised serum neurofilament light chain (sNfL) levels may indicate the presence of brain lesions with chronically active inflammation that are linked with more aggressive forms of multiple sclerosis (MS), a new study suggests.

People with high sNfL levels, the study revealed, had greater numbers of chronic inflammation lesions and pronounced nerve fiber damage.

The study, “Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis,” was published in Neurology.

MS lesions — areas of damage or scarring — in the brain or spinal cord occur when the immune system attacks the myelin sheath surrounding nerve fibers. Lesions may heal completely or partially, or in some cases, remain chronically inflamed around the edge of the lesion.

Lesions retaining inflammation around their edges are termed chronic active — or smoldering — lesions, depending on the extent of myelin damage, and are linked to more aggressive disease courses.

These lesions can be detected on MRI scans as lesions containing a paramagnetic — a weakly magnetic ­— rim, pertaining to the iron accumulation in activated immune cells. Such lesions are called paramagnetic rim MRI lesions (PRL).

Neurofilament proteins such as NfL are proteins that are released into the body’s fluids when neurons become damaged. NfL has been used as a marker for short-term neuronal damage in MS, but it remains unknown if this biomarker also could reflect the number of PRL lesions in patients.

To learn more, a team of researchers in Switzerland investigated whether sNfL levels are linked to PRL numbers and the severity of nerve fiber damage in people with MS.

Their study included a total of 118 adults with either relapsing-remitting MS (RRMS) or progressive MS, who were assessed from December 2017 to September 2019 at two university hospitals in Switzerland. Patients did not have recent relapses or new inflammatory lesions.

Among them, 75 participants (64%) had 0-1 PRL lesions, and the remaining 43 (35%) had two or more PRL lesions. Overall, participants with two or more lesions were significantly more disabled, as assessed by the Expanded Disability Status Scale (EDSS), and had a greater volume of T2 lesions (all MS lesions, PRL or others) than patients with fewer PRL lesions.

Additional findings also demonstrated that serum NfL levels were significantly higher in patients with more PRL lesions, regardless of any other clinical measure — such as disease type, use of disease-modifying therapy, disability score, and total lesion load.

“Our multicentre study provides clear evidence of a relationship between the presence of at least two PRL and higher levels of sNFL in MS patients (both RRMS and PMS) without acute disease activity,” the researchers wrote.

Brain volume among participants also was similar despite differences in PRL numbers, suggesting that “brain volume measurements — unlike PRL detection — do not provide a reliable snapshot of ongoing [nerve fiber] destruction at the time of MRI,” the team wrote.

In addition, participants with at least two PRL lesions had higher MS severity scores (MSSS) than those with fewer lesions, and this was “independent from factors known to influence clinical outcomes in MS, such as T2-lesion load and very-high-efficacy disease-modifying therapy.”

The team conducted additional exams on postmortem tissues of 20 MS patients and found that active and smoldering lesions had damaged nerve fibers (axons) at the site of inflammation, which rarely was observed on chronic lesions without active inflammation.

“Our postmortem evaluation shows that the histological [tissue structure] correlates of PRL — chronic active and smoldering lesions — exhibit pronounced axon damage at the lesion edge, which colocalizes with chronic inflammatory cells,” the researchers wrote.

Study limitations the researchers highlighted included using serum samples that were several months old and a small study size.

But overall, the findings provide “evidence that chronically inflamed lesions on MRI (PRL) are associated with elevated sNfL in people living with MS,” the researchers concluded. “We postulate that PRL may be a substantial driver of [neuronal] damage and clinical disability in patients without clinical or radiological signs of inflammation.”