Phenotypic correlates of serum neurofilament light chain levels in amyotrophic lateral sclerosis

Abstract

ObjectiveTo investigate the relationship between serum levels of the neuroaxonal degeneration biomarker neurofilament light chain (NFL) and phenotype in ALS.Materials and methodsSerum NFL (sNFL) concentration was quantified in 209 ALS patients and 46 neurologically healthy controls (NHCs).ResultssNFL was clearly increased in ALS patients and discriminated them from NHCs with AUC = 0.9694. Among ALS patients, females had higher sNFL levels, especially in case of bulbar onset. sNFL was more increased in phenotypes with both upper (UMN) and lower motor neuron (LMN) signs, and particularly in those with UMN predominance, compared to LMN forms. At the same time, primary lateral sclerosis (PLS) had significantly lower levels compared to UMN-predominant ALS (AUC = 0.7667). sNFL correlated negatively with disease duration at sampling and ALSFRS-R score, positively with disease progression rate, differed among King’s stages, and was negatively associated with survival. It also correlated with clinical/neurophysiological indices of UMN and LMN dysfunction (Penn UMN Score, LMN score, MRC composite score, active spinal denervation score). On the contrary, sNFL was not associated with cognitive deficits nor with respiratory parameters. Notably, we found a negative correlation between sNFL and estimated glomerular filtration rate (eGFR).InterpretationWe confirm that ALS is characterized by increased sNFL levels, whose main determinant is the rate of degeneration of both UMNs and LMNs. sNFL is a biomarker of only motor, not of extra-motor, disease. The negative correlation with kidney function might reflect varying renal clearance of the molecule and deserves further investigation before introducing sNFL measurement as routine test in clinical care of ALS patients.

Multifocal motor neuropathy as a mimic of amyotrophic lateral sclerosis: Serum neurofilament light chain as a reliable diagnostic biomarker

“…9,11 Another study showed that serum NfL was not significantly different between early and late symptomatic phases. 15 In contradiction to previous studies, 30,31 we found no correlation between disease severity and NfL levels in ALS. This might be explained by discrepancies between cohorts, as we excluded patients with bulbar symptomatology or pronounced UMN involvement.…”

“…Both components are reflected in the ALSFRS-R score as measures of disease severity, and they are additionally known to be related to higher neurofilament levels. [31][32][33] Similarly, in MMN, we found no or weak, not relevant, correlations of serum NfL with disease duration and disease severity. This is in agreement with other studies on NfL levels in various forms of neuropathy, demonstrating NfL is only minimally elevated, 16,18 is not correlated to disease duration 34,35 and NfL levels are stable upon treatment.…”

“…This might be explained by discrepancies between cohorts, as we excluded patients with bulbar symptomatology or pronounced UMN involvement. Both components are reflected in the ALSFRS‐R score as measures of disease severity, and they are additionally known to be related to higher neurofilament levels 31–33 . Similarly, in MMN, we found no or weak, not relevant, correlations of serum NfL with disease duration and disease severity.…”

Elevated biomarkers of neural injury in older adults following head-down bed rest: links to cardio-postural deconditioning with spaceflight and aging

“…Considering that rising NfL levels signal the early onset of neural injury as well as many neurological complications (Ferreira-Atuesta et al, 2021;Verde et al, 2023), these data indicate that the HDBR is an effective model for weightlessness exposure in relation to neurological insults to the brain. We hypothesized that the headward fluid shifts observed in HDBR would predispose participants to this type of injury.…”

Abnormal energy metabolism in ALS: a key player?

“…These patients did not present any clinical signs or changes in neurofilament light chain (NfL) blood levels. NfL is considered as a good biomarker to define the presymptomatic stage in ALS as its elevation often precedes motor deficits [46,47]. Strikingly, the authors showed that presymptomatic ALS gene carriers display abnormal body composition, indicating elevated catabolism and loss of metabolically active cells compared to metabolically active tissue.…”