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NfL Levels Linked to Worse Disability in Real-World MS

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Elevations in serum neurofilament light chain levels (sNfL) in people with multiple sclerosis (MS) are significantly linked to worse neurologic function, clinical disability, and lower brain volumes, according to new findings from a large, diverse population of patients with MS.

“This is one of the largest studies to evaluate serum neurofilament light chain levels in people with MS,” first author Elias S. Sotirchos, MD, an assistant professor of neurology at Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News.

“An important strength of this cohort is that it is a real-world cohort of patients followed in US and European MS centers,” he said. “The study captures the diversity of the MS population, including demographics, comorbidities, lifestyle factors, and clinical characteristics that may otherwise not be captured in a clinical trial population.”

The research was presented at the virtual ACTRIMS Forum 2021, the annual meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.

Neurofilaments — neuron-specific proteins that release in response to neuroaxonal injury — have been observed to be elevated in a variety of neurologic disorders, and with a need for biomarkers in MS, there is high interest of their role in the disease. But  studies involving real-world, heterogeneous MS populations are lacking, the researchers note.

To take a broader look at the issue, Sotirchos and colleagues conducted a cross-sectional evaluation of 6968 people with MS in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS), a large network of MS centers in the United States and Europe.

Participants’ baseline serum neurofilament light chain levels were compared with those of 201 healthy controls in the cohort using a novel, high throughput immunoassay (Siemens Healthineers).

Of those with MS, 1202 (17.2%) showed elevated serum neurofilament light chain levels, above the age-specific 97.5th percentile derived from the healthy controls.

A look at key factors associated with elevations showed significant links to having progressive MS (odds ratio [OR] 1.63), non-White race (OR, 1.43), type 2 diabetes (OR, 1.89), and smoking (current vs never smoker, OR 1.49).

Associations with age and symptom duration were somewhat complex, but overall, younger patients and those with shorter disease duration had the highest frequency of elevated serum neurofilament light chain levels.

Interestingly, those with a higher body mass index (BMI) showed a reduced odds of having elevated serum neurofilament light chain levels (OR, 0.83 per 5 kg/m2 increase in BMI).

Evaluation of neuroperformance measures — including walking speed, manual dexterity and processing speed, and MRI data — showed that those with elevated serum neurofilament light chain levels had worse neurologic function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (P < .001 for all).

Sotirchos noted that the higher rates of elevations in younger people, also observed in previous clinical trials, may reflect higher early-stage disease activity.

“Generally, people who are younger and earlier in the course of disease tend to have more inflammatory disease activity in MS, and that could be what we’re capturing here, but we need to better understand the pathologic correlates of elevated sNfL,” he said.

The lower levels of neurofilament light chain with higher BMI, also recently reported in another study, likewise need further investigation, including in healthy controls, Sotirchos added.

“Having lower serum neurofilament light chain levels with increasing BMI could have to do with effects of blood volume and how the serum neurofilament light chain is distributed in the body,” he explained.

The findings suggest that interpretation of serum neurofilament light chain levels without accounting for BMI could result in false-negative or false-positive results, Sotirchos noted.

“It will be important to further evaluate this observation in control populations and account for BMI in neurofilament light chain reference ranges.”

Sotirchos added that the 17% rate of elevated serum neurofilament light chain levels seen in people with MS in the study is likely an underestimate.

“This is a cross-sectional study and represents one sample per patient, so it is a snapshot in time,” he said. “With the nature of MS, we know that people’s levels fluctuate over time.”

In addition, most patients were on disease-modifying therapy for MS, so serum neurofilament light chain elevations could have been suppressed.

Commenting on the findings, Jennifer Graves, MD, PhD, director of the UC San Diego Neuroimmunology Research Program, La Jolla, California, said the study is an important addition to the ongoing evidence on serum neurofilament light chain in MS.

“The current presented research importantly addresses the gaps we have in understanding how best to apply serum filament light chain levels to individual patients and not just using them to assess group level means of outcome measures,” she told Medscape Medical News.

“The MS PATHS collaborative is looking at multiple factors (in addition to MS activity) that drive serum neurofilament light chain levels so meaningful and practical cut-offs for what’s abnormal can be created,” said Graves, who also directs the Rady Children’s Pediatric MS Clinic in San Diego.

Graves noted that the findings on BMI were unexpected.

“Elevated BMI has been shown to be associated with greater brain atrophy and greater relapses and disability in MS participants, so to have an opposite effect with serum neurofilament light chain is interesting.

“My thoughts would be that obesity is somehow affecting measurable blood levels of this marker. I think it less likely BMI has a protective effect against neurodegeneration given the observations with other MS outcome measures,” she added. 

In terms of future directions, Sotirchos noted that the researchers are following the group longitudinally to further assess changes in neurofilament light chain over time, and will be looking at associations with longitudinal, clinical, and radiologic outcomes.

The current research, meanwhile, offers important insights in terms of developing precision reference ranges, he noted.

“It appears that reference ranges may need to account for sex, race, BMI and comorbid/lifestyle factors,” Sotirchos said, “in order to potentially improve the performance of serum neurofilament light chain as a biomarker in MS and other neurological diseases.”

The study received funding from Biogen and the MS PATHS network receives funding from Biogen. Sotirchos has served on scientific advisory boards for Alexion, Viela Bio and Genentech, and has received speaker honoraria from Viela Bio and Biogen. Graves has disclosed no relevant financial relationships.

ACTRIMS Forum 2021: Abstract S1.1. Presented February 25, 2021.

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