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. 2023 Mar 15:15:1132808.
doi: 10.3389/fnagi.2023.1132808. eCollection 2023.

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

Federico Verde  1   2 , Ilaria Milone  1 , Eleonora Colombo  1 , Alessio Maranzano  1 , Federica Solca  1 , Silvia Torre  1 , Alberto Doretti  1 , Francesco Gentile  3 , Arianna Manini  3 , Ruggero Bonetti  3 , Silvia Peverelli  1 , Stefano Messina  1 , Luca Maderna  1 , Claudia Morelli  1 , Barbara Poletti  1 , Antonia Ratti  1   4 , Vincenzo Silani  1   2 , Nicola Ticozzi  1   2
Affiliations

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

Federico Verde et al. Front Aging Neurosci. .

Abstract

Objective: To investigate the relationship between serum levels of the neuroaxonal degeneration biomarker neurofilament light chain (NFL) and phenotype in ALS.

Materials and methods: Serum NFL (sNFL) concentration was quantified in 209 ALS patients and 46 neurologically healthy controls (NHCs).

Results: sNFL 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).

Interpretation: We 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.

Keywords: amyotrophic lateral sclerosis (ALS); axon; biomarker; motor neuron disease (MND); neurofilament light chain (NFL).

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Conflict of interest statement

FV was Review Editor of Frontiers in Dementia. BP received compensation for consulting services and/or speaking activities from Liquidweb S.r.l.; she was Associate Editor of Frontiers in Neuroscience and Review Editor of Frontiers in Aging Neuroscience. VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., and Novartis Pharma AG, and receives or has received research supports from the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call; he was in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, and Frontiers in Neurology. NT received compensation for consulting services from Amylyx Pharmaceuticals and Zambon Biotech SA; he was Associate Editor of Frontiers in Aging Neuroscience. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Serum NFL levels in ALS patients and neurologically healthy controls. (A) sNFL levels in ALS patients and NHCs. Wide horizontal bars represent median values, narrower horizontal bars represent first and third quartiles. (B) ROC curve of the discrimination between ALS patients and NHCs. ALS, amyotrophic lateral sclerosis; AUC, area under the curve; CI, confidence interval; NFL, neurofilament light chain; NHCs, neurologically healthy controls; ROC, receiver operating characteristic; sNFL, serum neurofilament light chain.
Figure 2
Figure 2
Serum NFL levels in different ALS motor phenotypes. (A) sNFL levels in all individual motor phenotypes of ALS. (B) sNFL levels in the three grouped ALS motor phenotypes according to UMN or LMN impairment. (C) ROC curve for the discrimination between PLS and UMNp ALS. In (A,B) wide horizontal bars represent median values, narrower horizontal bars represent first and third quartiles. AUC, area under the curve; CI, confidence interval; LMN, lower motor neuron; NFL, neurofilament light chain; PLS, primary lateral sclerosis; PMA, progressive muscular atrophy; ROC, receiver operating characteristic; sNFL, serum neurofilament light chain; UMN, upper motor neuron; UMNp, upper-motor-neuron-predominant ALS.
Figure 3
Figure 3
Correlation between serum NFL levels and disease progression rate. DPR, disease progression rate; CI, confidence interval; NFL, neurofilament light chain; sNFL, serum neurofilament light chain.
Figure 4
Figure 4
Serum NFL levels in different King’s stages. Wide horizontal bars represent median values, narrower horizontal bars represent first and third quartiles. NFL, neurofilament light chain; sNFL, serum neurofilament light chain.
Figure 5
Figure 5
Correlations of serum NFL levels with clinical/neurophysiological indices of UMN and LMN dysfunction. (A) Correlation between sNFL and PUMNS. (B) Correlation between sNFL and LMN score. (C) Correlation between sNFL and composite MRC score. (D) Correlation between sNFL and active spinal denervation score. CI, confidence interval; LMN, lower motor neuron; MRC, Medical Research Council; NFL, neurofilament light chain; PUMNS, Penn Upper Motor Neuron Score; sNFL, serum neurofilament light chain; UMN, upper motor neuron.
Figure 6
Figure 6
Serum NFL levels in patients with and without oculomotor abnormalities. Wide horizontal bars represent median values, narrower horizontal bars represent first and third quartiles. NFL, neurofilament light chain; OMA+, patients with oculomotor abnormalities; OMA−, patients without oculomotor abnormalities; sNFL, serum neurofilament light chain.
Figure 7
Figure 7
Correlation between serum NFL levels and estimated glomerular filtration rate. CI, confidence interval; eGFR, estimated glomerular filtration rate; NFL, neurofilament light chain; sNFL, serum neurofilament light chain.
Figure 8
Figure 8
Association of serum NFL levels with survival. The two Kaplan–Meier curves refer to patients with sNFL levels ≤ and  >  the median value, respectively. CI, confidence interval; HR, hazard ratio; NFL, neurofilament light chain; sNFL, serum neurofilament light chain.
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