Elevated serum neurofilament light chain (sNfL) is a common occurrence in various pediatric neurological and systemic conditions. When effective treatments are administered, sNfL concentrations tend to decrease. However, the influence of age on sNfL levels hasn’t been well understood, and age-adjusted reference ranges have not been established for individuals under 18 years old. In a recent publication by Ahmed Abdelhak, Franziska Petermeier, Pascal Benkert, et al in The Lancet Neurology¹, researchers led by Professor Jens Kuhle made a significant advancement by developing age-adjusted sNfL reference curves that can aid in diagnosing and monitoring neurological conditions for children and adolescents.

The Question: Can a clinically relevant age-adjusted sNfL reference database for children and adolescents be established?

Neurological conditions constitute a significant contributor to the burden of pediatric disabilities worldwide. Accurate monitoring of neuroaxonal injury is important on both a population-wide scale and an individual patient level for applications such as early diagnosis of neurological disorders and clinical trial research.

An important indicator of neuroaxonal injury is the concentration of sNfL. This biomarker, specific to neuroaxonal damage, has garnered considerable attention as a potential game-changer in the management of pediatric neurological disorders. However, sNfL levels can vary depending on physiological factors and various pathological conditions, making the interpretation of sNfL measurements complex. The establishment of a reference database corrected for age and body-mass index for healthy adults² was a huge advancement in understanding blood NfL levels. This dataset proved useful in identifying individuals with multiple sclerosis (MS) at risk for a detrimental disease course and suboptimal therapy response². In line with these findings, Quanterix’s Simoa® NfL assay was granted Breakthrough Device designation by the U.S. Food and Drug Administration as a prognostic aid in assessing the risk of disease activity in patients diagnosed with relapsing-remitting MS³.

sNfL is elevated in several pediatric neurological and systemic conditions^4-7and decreases with effective treatments^8-10. However, no age-adjusted reference range exists for children and adolescents, hindering the wide-scale application of sNfL as a biomarker for pediatric populations in clinical and research settings. Thus, the goal of this study was to establish an age-adjusted sNfL reference database using immunoassay data in a large population of healthy children and adolescents and assess the clinical application of the reference dataset in children and adolescents with various neurological diseases.

The Approach

To compile pediatric sNfL reference dataset, sNfL was measured in 2,667 healthy children and adolescents, spanning ages 0 to 22 years. This data was sourced from two international cohorts: the Coronavirus Antibodies in Kids from Bavaria study in Germany, and a pediatric case-control cohort from the US Network of Pediatric Multiple Sclerosis Centers in North America. Exclusions were made for children with ongoing or past COVID-19 infection, positive SARS-CoV-2 antibody status during sampling, or a history of primary systemic or neurological conditions. The relationship between sNfL levels, age, and weight was retrospectively examined using linear models. This methodology enabled the researchers to establish reference percentiles and Z score values. To evaluate the clinical utility of the new age-adjusted sNfL reference values, sNfL levels were measured in 220 children and adolescents with neurological diseases. sNfL levels were measured using the Simoa® NfL assay on Quanterix’s HD-X™ Automated Immunoassay Analyzer. Simoa® technology has delivered the gold standard for earlier biomarker detection in blood, serum, or plasma, with the ability to quantify proteins that are far lower than the Limit of Quantification of conventional analog methods. Its industry-leading precision instruments, digital immunoassay technology and CLIA-certified Accelerator laboratory have supported research that advances disease understanding and management in neurology, oncology, immunology, cardiology and infectious disease. 

Landmark Breakthrough: Establishing Normative Reference Values for sNfL in Children and Adolescents

The study’s findings showcase the intricate relationship between sNfL concentrations and age. In healthy children and adolescents, sNfL concentrations exhibit a marked decrease with age in children until a critical inflection point at around 10.3 years. Beyond this point, sNfL concentrations stabilize up to age 22, signaling an age-independent phase. Notably, the influence of body weight on sNfL concentrations, while present, remained marginal in comparison to age. This revelation enhances our comprehension of the multifaceted factors influencing sNfL concentrations in the pediatric population.

Z score is Superior in Differentiating Healthy Children and Adolescents

The clinical utility of the reference database was validated in children and adolescents with neurological conditions. Both raw sNfL concentrations and sNfL Z scores were elevated in the pediatric population with neurological conditions, but sNfL Z scores were associated with larger difference between the healthy population, suggesting that Z scores may have greater distinctive power between various neurological diseases and healthy children and adolescents. These Z scores have emerged as a powerful tool to facilitate measurement of neuroaxonal damage. In a realm where accurate diagnosis and monitoring are paramount, the Z scores offer a breakthrough, potentially enabling more accurate assessments and tailored interventions.

Looking Ahead: A Promising Horizon

The study’s profound insights into sNfL concentrations and their age-related dynamics, coupled with the transformative role of Simoa® technology ushers in a new era of pediatric neurology. By establishing age-adjusted sNfL reference values and unleashing the potential of Z scores, this study serves as a significant advancement for researchers, clinicians and families navigating the complexities of pediatric neurological conditions. With the urgent need for noninvasive, accessible, scalable, and cost-effective biomarkers to aid in early diagnosis and treatment and disease monitoring, this study could lay the foundation for advancements in research, treatments, diagnostics, interventions, and improved quality of life for children with neurological disorders worldwide.

References:

1. Abdelhak A, Petermeier F, Benkert P, et al. Serum neurofilament light chain reference database for individual application in pediatric care: a retrospective modelling and validation study [published online ahead of print, 2023 Jul 28]. Lancet Neurol. 2023;S1474-4422(23)00210-7. doi:10.1016/S1474-4422(23)00210-7
2. Benkert P, Meier S, Schaedelin S, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022;21(3):246-257. doi:10.1016/S1474-4422(22)00009-6
3. Quanterix granted breakthrough device designation from U.S. FDA for NFL test for multiple sclerosis. Quanterix. August 16, 2022. Accessed August 15, 2023. https://www.quanterix.com/press-releases/quanterix-granted-breakthrough-device-designation-from-us-fda-for-nfl-test-for-multiple-sclerosis/
4. Depoorter A, Neumann RP, Barro C, et al. Neurofilament Light Chain: Blood Biomarker of Neonatal Neuronal Injury. Front Neurol. 2018;9:984. Published 2018 Nov 20. doi:10.3389/fneur.2018.00984
5. Wong YYM, Bruijstens AL, Barro C, et al. Serum neurofilament light chain in pediatric MS and other acquired demyelinating syndromes. Neurology. 2019;93(10):e968-e974. doi:10.1212/WNL.0000000000008057
6. van der Vuurst de Vries RM, Wong YYM, Mescheriakova JY, et al. High neurofilament levels are associated with clinically definite multiple sclerosis in children and adults with clinically isolated syndrome. Mult Scler. 2019;25(7):958-967. doi:10.1177/1352458518775303
7. Byrne LM, Schultz JL, Rodrigues FB, et al. Neurofilament Light Protein as a Potential Blood Biomarker for Huntington’s Disease in Children. Mov Disord. 2022;37(7):1526-1531. doi:10.1002/mds.29027
8. Olsson B, Alberg L, Cullen NC, et al. NFL is a marker of treatment response in children with SMA treated with nusinersen. J Neurol. 2019;266(9):2129-2136. doi:10.1007/s00415-019-09389-8
9. Wurster CD, Steinacker P, Günther R, et al. Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen. J Neurol. 2020;267(1):36-44. doi:10.1007/s00415-019-09547-y
10. Reinert MC, Benkert P, Wuerfel J, et al. Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2020;7(4):e749. Published 2020 May 13. doi:10.1212/NXI.0000000000000749