Associations of sNfL with clinico‐radiological measures in a large MS population

Abstract

Objective Evaluation of serum neurofilament light chain (sNfL), measured using high‐throughput assays on widely accessible platforms in large, real‐world MS populations, is a critical step for sNfL to be utilized in clinical practice. Methods Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high‐throughput, scalable immunoassay. Results Elevated sNfL levels for age (sNfL‐E) were found in 1238 MS participants (17.8%). Factors associated with sNfL‐E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease‐modifying therapy was associated with lower odds of sNfL‐E. MS participants with sNfL‐E exhibited worse neurological function (patient‐reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short‐term rates of whole brain atrophy in sNfL‐E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL‐E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age‐normative sNfL Z‐scores as a continuous variable. Interpretation Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.

Agreement Between Published Reference Resources for Neurofilament Light Chain Levels in People With Multiple Sclerosis

“…6,9 Six published reference populations were used to classify NfL as elevated or normal. [2][3][4][5][6][7] The reference resource characteristics are summarized in Table 1. One resource adjusted for BMI, which was available for all included MS PATHS participants.…”

Emerging imaging and liquid biomarkers in multiple sclerosis

“…In addition to aiding in diagnosis, sNfL may also be a biomarker for both concomitant and future disease activity. Several studies have shown that sNfL correlates with disease activity and baseline MRI lesion burden and can predict future acute clinical activity and new gadolinium-enhancing and T2 MRI lesions [75,76,80,[84][85][86][87], as well as future brain and spinal cord atrophy and disability worsening [75,[84][85][86][87][88]. Consistent with sNfL's role as a disease activity indicator, DMT use correlates with lower sNfL levels.…”

“…Although sNfL may be a useful biomarker across several aspects of MS care, to date, sNfL has largely been investigated on a group level and only a handful of studies have looked at predictions on an individual level. Interpretations of individual sNfL levels are also complicated by several common factors that associate with higher sNfL levels, including age, body mass index, impaired renal function, diabetes mellitus, and active smoking, underscoring the need for normative sNfL data to correct for these factors [84,87,94]. Prospective clinical use of sNfL on an individual MS patient level has not yet been established.…”

Challenges and Opportunities for the Promising Biomarker Blood Neurofilament Light Chain

“…However, with many emerging reference healthy population data sets for NfL values, it has become evident that each delivers a different definition for the normal range and upper limit of normal. 2,6,7 International collaborations to define a reference data set representative of the world's diverse population are needed, one that does not reflect only people of European ancestry or those residing in Europe and North America. An ideal reference healthy population would include thousands of participants worldwide.…”

“…Such approaches, which are capable of generating age- and BMI-adjusted NfL values, represent a significant step toward a more contextualized interpretation of NfL level and could aid physicians and researchers in interpreting values acquired on different analytical platforms. However, with many emerging reference healthy population data sets for NfL values, it has become evident that each delivers a different definition for the normal range and upper limit of normal …”