Abstract
Objective: To assess whether phosphorylated neurofilament heavy chain (pNfH) can discriminate different upper motor neuron (UMN) syndromes, namely, ALS, UMN-predominant ALS, primary lateral sclerosis (PLS) and hereditary spastic paraparesis (hSP) and to test the prognostic value of pNfH in UMN diseases. Methods: CSF and serum pNfH were measured in 143 patients presenting with signs of UMN and later diagnosed with classic/bulbar ALS, UMNp-ALS, hSP, and PLS. Between-group comparisons were drawn by ANOVA and receiver operating characteristic (ROC) analysis was performed. The prognostic value of pNfH was tested by the Cox regression model. Results: ALS and UMNp-ALS patients had higher CSF pNfH compared to PLS and hSP (p < 0.001). ROC analysis showed that CSF pNfH could differentiate ALS, UMNp-ALS included, from PLS and hSP (AUC = 0.75 and 0.95, respectively), while serum did not perform as well. In multivariable survival analysis among the totality of UMN patients and classic/bulbar ALS, CSF pNfH independently predicted survival. Among UMNp-ALS patients, only the progression rate (HR4.71, p = 0.01) and presence of multifocal fasciculations (HR 15.69, p = 0.02) were independent prognostic factors. Conclusions: CSF pNfH is significantly higher in classic and UMNp-ALS compared to UMN diseases with a better prognosis such as PLS and hSP. Its prognostic role is confirmed in classic and bulbar ALS, but not among UMNp, where clinical signs remained the only independent prognostic factors.
Highlights
Syndromes presenting with upper motor neuron (UMN) signs include diseases with very variable prognosis, ranging from “pure” UMN diseases to UMN-predominant presentation of amyotrophic lateral sclerosis (ALS) [1]
As part of our systematized neurological assessment, for this study we considered several clinical signs of MN dysfunction that were detected at sampling time: fasciculations frequency and distribution, presence of Babinski and Hoffman signs as well as Achilles clonus, exaggerated masseter reflex, presence of frontal release signs, pseudobulbar affect [10] and presence of cramps
When multivariate regression analysis was performed on the variables that were significant at univariate analysis, the following remained in the model: cerebrospinal fluid (CSF) concentration of phosphorylated neurofilament heavy chain (pNfH) (HR 13.93, p = 0.001; 95% coefficient of 0.09 (CI) 2.93–66.18), time to generalization (HR 0.97, p = 0.006; 95% CI 0.96–0.99), presence of dementia (HR 4.03, p < 0.001; 95% CI 1.89–8.59), ALSFRS-R
Summary
Neurofilaments are major axonal cytoskeleton proteins that are essential for the structural stability of myelinated axons and for reaching the optimal propagation speed of electrical impulses These proteins are released from damaged or diseased axons both in cerebrospinal fluid (CSF) and blood and have been proposed as diagnostic or prognostic biomarkers for ALS and other neurodegenerative conditions [8,9]. We measured pNfH levels in CSF and serum of patients presenting with UMN signs, who were later diagnosed within a definite clinical group (classic or bulbar ALS, UMNp-ALS, PLS, hSP) with subsequent diagnostic confirmation after a long follow-up period (median: 85 months). This study was designed to investigate whether pNfH can be used as a complementary tool for differential diagnosis in patients presenting with UMN syndromes and to help reduce diagnostic delay in UMN syndromes
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