Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element‑Binding Protein Concentration

Abstract

Introduction: Prevision of conversion from clinically isolated syndrome (CIS) tomultiple sclerosis (MS) is required to avoid unnecessary use of immunomodulatingagents and to recognize patients with high disease activity. Our aim was toevaluate the value of phosphorylated neurofilament heavy chain (pNFH, a markerfor neuroaxonal degeneration) and Cyclic adenosine monophosphate responseelement‑binding protein (cAMP response element‑binding protein [CREB], amarker for neuroregeneration) levels in the prediction of conversion from CIS toMS. Methods: Twenty‑three consecutively recruited treatment‑naïve CIS patientswere followed for 36 months. pNFH and CREB levels were measured in the firstepisode cerebrospinal fluid (CSF) and the serum of 12 converting (CIS‑MS) and11 nonconverting CIS patients (CIS‑CIS) by enzyme‑linked immunosorbent assay.Results: Baseline CSF but not serum samples of CIS‑CIS patients displayedsignificantly lower pNFH levels compared to patients with CIS‑MS. The analysisof receiver operating characteristic curve presented a high specificity for theprediction of MS conversion for the CSF pNFH cut‑off level of 730.9 pg/ml. CSFpNFH levels significantly correlated with serum and CSF CREB levels. Higherbaseline CSF pNFH and CREB levels were associated with more rapid progressionto MS or increased disability scores. Conclusion: CSF pNFH measurement maypotentially determine MS patients with unfavorable clinical progression after thefirst attack. pNFH and CREB appear to be increased in parallel in CSF of CISpatients with higher disease activity. These results suggest that neurofilaments arenot only indicators of axonal degeneration but also partly a marker of neuronaldifferentiation and new axon regeneration mediated by CREB signaling pathway.