Neurofilament light: A candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion

Abstract

Objective: To evaluate neurofilament light (NfL) as a biomarker of the presymptomatic phase of amyotrophic lateral sclerosis (ALS).

Methods: The study population includes 84 individuals at risk for developing ALS, 34 controls, 17 ALS patients, and 10 phenoconverters (at-risk individuals observed both before and after the emergence of clinically manifest disease). At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation (in SOD1, C9orf72, TARDBP, FUS, VCP, etc), but who, at the time of enrollment, demonstrated no clinical symptoms or signs (including electromyographic evidence) of manifest disease. NfL in serum and cerebrospinal fluid (CSF) were quantified using an electrochemiluminescence immunoassay.

Results: Serum and CSF NfL are substantially higher in ALS patients compared to controls and at-risk individuals and remain relatively stable over time. Among phenoconverters, however, NfL levels were elevated (ie, above the range observed in controls) as far back as ∼12 months preceding the emergence of the earliest clinical symptoms or signs of disease.

Interpretation: Serum (and CSF) NfL are informative biomarkers of presymptomatic ALS, providing a new tool to quantify presymptomatic disease progression and to potentially predict the timing of clinical phenoconversion. As such, quantification of NfL may aid the design and implementation of early therapeutic intervention for affected individuals and/or disease prevention trials for individuals at short-term risk of developing ALS. Ann Neurol 2018 Ann Neurol 2018;83:130-139.

Figure 1

Baseline levels of NfL in serum and CSF: (a) serum NfL (pg/ml); (b) log-transformed serum NfL; (c) CSF NfL (pg/ml); and (d) log-transformed CSF NfL. Boxes show median, and 25^th and 75^th percentiles; whiskers extend to a maximum of 1.5 x interquartile range (IQR), or to the most extreme value if it is less than 1.5 x IQR from the 25^th or 75^th percentile.

Figure 2

Longitudinal changes in serum NfL concentration (pg/ml): (a) controls; (b) at-risk individuals who remain pre-symptomatic throughout follow-up; (c) phenoconverters; and (d) ALS patients. The x-axis in (a) and (b) shows years since baseline. The x-axis in (c) and (d) shows years to or since the onset of symptoms or signs, which is marked by the vertical dashed line at year=0.

Figure 3

Longitudinal changes in serum NfL concentration, natural log-transformed: (a) phenoconverters; and (b) ALS patients. The x-axis shows years to or since the onset of symptoms or signs, which is marked by the vertical dashed line at year=0. The gray area covers the range of serum NfL values observed in the control group. The closed circles mark the elevated levels of NfL (i.e. above the highest value seen in controls) that were measured in serum collected before the onset of symptoms or signs.

Figure 4

Scatterplot of baseline serum NfL levels vs. baseline age shows that, although NfL levels are slightly higher among older individuals in the control (open circles) and at-risk groups (open triangles), the magnitude of this increase is negligible in comparison to the levels of NfL observed among ALS (closed squares) patients (i.e. older age does not explain the increase in serum NfL among ALS patients). Open circles represent controls; open triangles represent at-risk individuals who remain pre-symptomatic throughout follow-up; and filled squares represent ALS patients. Vertical dashed lines demarcate age groups (< 40, 40-60 and > 60 years of age).