Neurofilament Light Chain in Cerebrospinal Fluid As a Novel Biomarker in Evaluating Both Clinical Severity and Therapeutic Response in Niemann-Pick Disease Type C1

Purpose: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal disorder caused by pathogenic variants in NPC1. Disease progression is monitored using the NPC Neurological Severity Scale, but there are currently no established validated or qualified bio-markers. Neurofilament light chain (NfL) is being investigated as a biomarker in multiple neurodegenerative diseases. Methods: Cross-sectional and longitudinal cerebrospinal fluid (CSF) samples were obtained from 116 individuals with NPC1. NfL levels were measured using a solid-phase sandwich enzyme -linked immunosorbent assay and compared with age-appropriate non-NPC1 comparison samples. Results: Median levels of NfL were elevated at baseline (1152 [680-1840] pg/mL) in NPC1 compared with controls (167 [82-372] pg/mL; P < .001). Elevated NfL levels were associated with more severe disease as assessed by both the 17-domain and 5-domain NPC Neurological Severity Score. Associations were also observed with ambulation, fine motor, speech, and swallowing scores. Although treatment with the investigational drug 2-hydroxypropyl-beta-cyclodextrin (adrabetadex) did not decrease CSF NfL levels, miglustat therapy over time was associated with a decrease (odds ratio = 0.77, 95% CI = 0.62-0.96). Conclusion: CSF NfL levels are increased in individuals with NPC1, associated with clinical disease severity, and decreased with miglustat therapy. These data suggest that NfL is a biomarker that may have utility in future therapeutic trials. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.