Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study

Abstract

Background: Patients presenting with upper motor neuron (UMN) signs may widely diverge in prognosis, ranging from amyotrophic lateral sclerosis (ALS) to primary lateral sclerosis (PLS) and hereditary spastic paraplegia (hSP). Neurofilaments are emerging as potential diagnostic and prognostic biomarkers for ALS, but the diagnosis of UMN syndromes still relies mostly on clinical long-term observation and on familiarity or genetic confirmation. Objectives: To test whether phosphorylated neurofilament heavy chain (pNfH) may discriminate different UMN syndromes at diagnosis and to test their prognostic role among these diseases. Methods: We measured the cerebrospinal fluid (CSF) and serum pNfH of 30 patients presenting with UMN signs and diagnosed with ALS, hSP, and PLS, plus 9 healthy controls (HC). Results: ALS patients had higher levels of pNfH in CSF and serum compared to HC (p < 0.001 and p < 0.001 in CSF and serum, respectively) and PLS (p = 0.015 and p = 0.038) and hSP (p = 0.003 and p = 0.001) patients. PLS and hSP patients had similar CSF and serum pNfH concentrations, but a higher CSF pNfH concentration, compared to HC (p = 0.002 and p = 0.003 for PLS and hSP, respectively). Receiver operating characteristic curves for discriminating ALS from PLS and hSP showed an area under the curve of 0.79 for CSF and 0.81 for serum. In multivariable survival analysis including relevant clinical factors CSF pNfH represented the strongest variable predicting survival (HR 40.43; 95% CI 3.49–467.79, p = 0.003) independently of clinical group. Conclusions: Despite some statistical instability of the results due to limitations in sample size, our study supports the role of CSF pNfH as a prognostic biomarker for motor neuron diseases presenting with UMN signs. A potential power to discriminate between ALS and other UMN syndromes at presentation, and between all of the examined MND and HC, has been detected for both CSF and serum pNfH.

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

“…For a more detailed overview of studies analysing differential specificities of NFs in serum and CSF see Table 1. In contrast, slowly progressing MNDs such as hereditary spastic paraplegia [73,74], spinal and bulbar muscular atrophy [75], and, possibly, PLS [74] showed close to normal levels of NFs, a finding which can help to rule out ominous conditions such as ALS. Though promising, these results require an inter-laboratory validation and their confirmation in larger patient cohorts.…”

“…Cross-sectional levels of NFs are generally measured at different time points from the onset of disease, without full knowledge of their longitudinal behaviour. Of course, the diagnosis of each of these conditions has by itself robust prognostic implications, when compared to ALS [74].…”

Diagnostic and Prognostic Role of Blood and Cerebrospinal Fluid and Blood Neurofilaments in Amyotrophic Lateral Sclerosis: A Review of the Literature

“…Almost all the studies investigating both CSF and blood compartments on ALS patients have showed high correlation between CSF and blood Nfs concentrations, with increased Nfs levels than in blood [7,8,9,10,11,12,13].…”

“…The most relevant finding of the study lead by Zucchi et al was that CSF and serum p-NfH can discriminate ALS with predominant UMN signs from other UMN syndromes, like hereditary spastic paraplegia (hSP) and primary lateral sclerosis (PLS); moreover, CSF p-NfH concentration may differentiate UMN syndromes from HC and are the most stronger predictors of survivals [9].…”

Altered CSF levels of monoamines in hereditary spastic paraparesis 10

“…13 Furthermore, elevated CSF levels of phosphorylated neurofilament heavy chain in patients with HSP (n = 9) compared with controls have been reported in a previous study. 14 It will be interesting to study NFL levels in patients with ALS harboring KIF5A mutations.…”