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. 2025 Jul 7:3:103443.
doi: 10.1016/j.gimo.2025.103443. eCollection 2025.

Serum neurofilament light protein as a biomarker in Niemann-Pick disease, type C1

Niamh X Cawley  1 , Ruyu Zhou  2 , Avani Mylvara  1 , Cameron J Padilla  1 , Derek Alexander  1 , Nicole Farhat  1 , Carolina Alvarez  1 , Antony Cougnoux  1 , Elizabeth Berry-Kravis  3 , Stephanie M Cologna  4 , Fang Liu  2 , Forbes D Porter  1
Affiliations

Serum neurofilament light protein as a biomarker in Niemann-Pick disease, type C1

Niamh X Cawley et al. Genet Med Open. .

Abstract

Purpose: Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disease caused by pathological variants in NPC1. Analysis of serum neurofilament light (NfL), a marker of neuronal damage, could be useful as a biomarker for patient monitoring and clinical trial design.

Methods: We measured NfL levels in serum samples from 118 well-characterized individuals with NPC1 and analyzed them with respect to clinical measures and treatment status.

Results: The results show a 6.1-fold increase in serum NfL in individuals with NPC1 compared with age-appropriate controls. Moreover, serum NfL levels showed a significant positive correlation with age of neurological symptom onset and the annual severity increment score. Serum NfL levels were also positively correlated with the 17- and 5-domain NPC Neurological Severity Scores. Longitudinal analyses reveal a 26% reduction in serum NfL levels in individuals on miglustat, a therapeutic drug used off-label for the treatment of NPC1 in the United States of America. Effectiveness of intrathecal hydroxypropyl-β-cyclodextrin treatment may be more beneficial in younger individuals. To help inform clinical trial design, our modeling predicts that a measurable reduction of serum NfL levels might be observed after 8 months of treatment with a potential drug exhibiting 10% to 20% efficacy.

Conclusion: Our data suggest that NfL may be a useful serum biomarker for NPC1.

Keywords: Hydroxypropyl-β-cyclodextrin; Miglustat; Neurofilament light; Niemann-Pick disease; Serum biomarker.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Serum NfL levels in individuals with NPC1 and control individuals. A. Baseline levels of NfL in individuals with NPC1 compared with age-appropriate control individuals. Included also are the baseline NfL levels from the 9 asymptomatic individuals. Additionally, analysis of individuals with NPC1 treated or not with miglustat and analysis of baseline data stratified into 4 age groups as defined by Vanier et al. B. Correlation graph of CSF versus serum NfL level. C and D. Correlation graph of serum NfL levels and age of neurological onset (ANO) in all individuals analyzed (C) and in individuals <30 years of age (D). E and F. Correlation graphs of serum NfL levels with ASIS (E) and NSS (F). ASIS, annual severity increment score; CSF, cerebrospinal fluid; NfL, neurofilament light; NPC1, Niemann-Pick disease, type C1; NSS, Neurological Severity Score.
Figure 2
Figure 2
Results of longitudinal analysis of log(serum NfL) using linear mixed-effects model (109 participants totaling 233 measurements). A. Table representing a summary of the statistical analyses. The expression a(exponentiated(estimated coefficient) − 1) × 100% reflects the percentage change in serum NfL levels for a 1-unit increase in the covariate. For example, an estimated coefficient of 0.74 for miglustat indicates that serum NfL levels decrease by 26% with miglustat treatment compared with without it. B. Forest plot of the effects of baseline age, time, ANO, sex, and treatment with miglustat, intrathecal HPβCD (adrabetadex, VTS270), and arimoclomol on serum NfL levels. ANO, age of neurological onset; HPβCD, hydroxypropyl-beta-cyclodextrin; NfL, neurofilament light.
Figure 3
Figure 3
Serum NfL levels in individuals with NPC1 treated with IT HPβCD. A. Serum NfL levels in 17 individuals with NPC1 before and after IT HPβCD treatment. B. The 17 individuals were divided into those that had a calculated increase or decrease in NfL levels and plotted as the difference between before and after treatment normalized to the time interval between before and after treatment in years. Note that 5 of the 17 individuals showed small annual rates of change in serum NfL (green circles). Of the remainder, 3 of the 4 “responders” in the group showing a decrease in NfL received IT HPβCD treatment at <10 years of age (blue circles). In contrast, of the 8 remaining “nonresponders” showing an increase, 2 received IT HPβCD treatment at <10 years of age (orange circles). HPβCD, hydroxypropyl-beta-cyclodextrin; IT, intrathecal; NfL, neurofilament light; NPC1, Niemann-Pick disease, type C1.
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