Phosphorylated Neurofilament Heavy Chain Levels In Paired Plasma And CSF Of Amyotrophic Lateral Sclerosis

Background and objective:Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by degeneration of both upper and lower motor neurons. In this study, we aimed to measure both plasma and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain (pNF-H) levels in patients with ALS, and determine if there is a correlation. We also evaluated plasma and CSF pNF-H levels to investigate if this biomarker could predict the time to generalization (TTG) in ALS better.Methods:Paired plasma and CSF pNF-H levels of patients with ALS (n=51), multiple system atrophy (n=12) and controls (n=30) were measured by monoclonal sandwich ELISA. TTG, which also indicates the time of symptoms spreading from spinal or bulbar localization to both, was evaluated in all ALS patients.Results:1.The median plasma pNF-H level was 1.41ng/ml,0.86ng/ml and 0.28ng/ml for ALS, MSA and HC respectively while the median CSF pNF-H level was 1.55ng/ml, 0.60ng/ml and 0.37ng/ml, respectively. The plasma pNF-H level was significantly higher in ALS than in MSA (p=0.046) and healthy controls (p<0.001); the CSF pNF-H level was significantly higher in ALS than in MSA (p=0.002) and/or healthy controls (p< 0.001).2. The sensitivity of pNF-H in plasma is 80.39% and the specificity is 73.81%. The sensitivity of pNF-H in CSF is 82.35% and the specificity is 73.81%.3.In ALS patients, there was no significant difference between males and females in pNF-H levels (plasma:p=0.750; CSF:p=0.429). Of note, the median CSF pNF-H level was relatively higher in patients with bulbar onset (p=0.038), but there was no association between plasma pNF-H levels and the site of onset (p=0.437). A weak correlation between CSF pNF-H levels and ALSFRS-r (r=-0.347, p=0.013) was found, but there was no correlation found between plasma pNF-H levels and ALSFRS-r at the time of sample collection (p=0.213). Meanwhile, a significant correlation was observed between progression rate and pNF-H levels (plasma:r=0.535,p<0.001; CSF:r=0.617,p< 0.001).4.We found a strong correlation between plasma and CSF pNF-H levels within individual patients(r= 0.712, p< 0.001).5.The mean TTG in ALS patients was 22.9± 2.5 months, and there was an inverse correlation between plasma(r=-0.661; p< 0.001)/CSF (r=-0.869; p< 0.001) pNF-H levels and TTG.Conclusion:1.The correlation of plasma and CSF pNF-H levels would bring insight into the pathogenesis of ALS.2. TTG might play an important role in the future study of ALS, as an early indicator of survival.