Development of an age‐adjusted model for blood neurofilament light chain

Abstract

Objective To develop an age‐adjustment model for neurofilament light chain (NfL), an emerging injury marker in patients with a range of neurologic conditions including multiple sclerosis (MS). Methods Serum and plasma samples were collected from a healthy donor (HD) cohort of 118 individuals aged 24 to 66 years, 90 patients with relapsing MS (RMS) and 22 patients with progressive MS (PMS). Serum and plasma samples were assessed for NfL using the SIMOA assay (Quanterix NfL Advantage Kit™). A log‐linear model was used to evaluate the relationship between NfL and age and to calculate age‐adjusted NfL levels. Results Higher serum and plasma NfL levels were significantly associated with increasing HD age. Log‐transformation of blood NfL levels reduced heteroscedasticity and skewness. A log‐linear model enabled adjustment for age‐related increase in serum and plasma NfL levels (2.3% [95% CI, 1.6–2.9] and 2.6% [95% CI, 1.3–3.3] per year, respectively). Following age adjustment, NfL did not show significant association with HD sex or ethnicity. While unadjusted serum NfL levels were elevated in patients with PMS (mean age 56 years) compared with those with RMS (mean age 37 years), age‐adjusted NfL levels did not differ. Interpretation A log‐linear, age adjustment model was developed to enable comparison of NfL levels across populations with different ages. While additional data and evidence are needed for patient‐level adoption, this could be a valuable tool for interpreting NfL levels across a range of patient groups with neurologic conditions.

Age‐ and disease‐specific reference values for neurofilament light presented in an online interactive support interface

“…These data formed the input for the fitted 5th to 95th percentile values per age and disorder for the support interface. In the reference control population, blood NfL values (median [5th-95th percentile]) ranged from 5 [3][4][5][6][7][8][9][10] pg/mL at age 30 to 19…”

“…Agespecific interpretations have been proposed, but none of the previous studies included a large age range with both cerebrospinal fluid (CSF) and blood, or multiple diseases. [4][5][6][7][8] To increase the interpretability of test results, we This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.…”

“…Therefore, a single reference value or cut‐off cannot be defined, which hampers use of NfL results in clinical practice. Age‐specific interpretations have been proposed, but none of the previous studies included a large age range with both cerebrospinal fluid (CSF) and blood, or multiple diseases 4–8 . To increase the interpretability of test results, we developed an online interactive interface to provide reference values in relation to age and clinical context that was evaluated by clinicians.…”

Neurofilament light chain in blood as a diagnostic and predictive biomarker for multiple sclerosis: A systematic review and meta-analysis

“…A total of 31 studies fulfilling the inclusion and exclusion criteria were finally included in quantitative analysis ( Fig 1 ) [ 10 , 11 , 13 , 14 , 25 – 51 ]. Among them, 28 studies comprising 6545 MS patients and 2477 controls were eligible for meta-analysis of diagnosis value ( Table 1 ), and 5 studies with 4444 MS patients were synthesized in meta-analysis of predictive value ( S1 Table ).…”

“…These results indicate that age-specific reference of blood NfL should be established. Recently, several studies have tried to construct an age- and/or BMI-adjusted model for sNfL [ 16 , 51 ]. Using multiple large datasets, Benkert et al established an age- and BMI-corrected reference database of sNfL values, and further showed the merit of sNfL percentiles and Z scores in predicting disease course and response to DMT [ 16 ].…”