CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis

Abstract

Elevated cerebrospinal fluid (CSF), Neurofilament Light (NF-L) and phosphorylated Heavy (pNF-H) chain levels have been found in Amyotrophic Lateral Sclerosis (ALS), with studies reporting a correlation of both neurofilaments (NFs) with the disease progression. Here, we measured NF-L and pNF-H concentrations in the CSF of ALS patients from a single tertiary Center and investigated their relationship with disease-related variables. A total of 190 ALS patients (Bulbar, 29.9%; Spinal, 70.1%; M/F = 1.53) and 130 controls with mixed neurological diseases were recruited. Demographic and clinical variables were recorded, and ΔFS was used to rate the disease progression. Controls were divided into two cohorts: (1) patients with non-inflammatory neurological diseases (CTL-1); (2) patients with acute/subacute inflammatory diseases and tumors, expected to lead to significant axonal and tissue damage (CTL-2). For each patient and control, CSF was taken at the time of the diagnostic work-up and stored following the published guidelines. CSF NF-L and pNF-H were assayed with commercially available ELISA-based methods. Standard curves (from independent ELISA kits) were highly reproducible for both NFs, with a coefficient of variation < 20%. We found that CSF NF-L and pNF-H levels in ALS were significantly increased when compared to CTL-1 (NF-L: ALS, 4.7 ng/ml vs CTL-1, 0.61 ng/ml, p < 0.001; pNF-H: ALS, 1.7 ng/ml vs CTL-1, 0.03 ng/ml, p < 0.0001), but not to CTL-2. Analysis of different clinical and prognostic variables disclosed meaningful correlations with both NF-L and pNF-H levels. Our results, from a relatively large ALS cohort, confirm that CSF NF-L and pNF-H represent valuable diagnostic and prognostic biomarkers in ALS.

Correlations between serum and CSF pNfH levels in ALS, FTD and controls: a comparison of three analytical approaches

“…Our results support previous findings that CSF neurofilament levels cannot differentiate ALS patients according the site of onset (spinal or bulbar) [195], suggesting that the extent of ongoing neuronal degeneration is similar in both types of onset, despite the poorer prognosis in bulbar onset patients. In some way, the worse prognosis in bulbar onset cases could be in part due to the earlier dysphagia, which in turn would affect the nutritional intake and by extension influence the course of the disease due to the increased metabolic demand present in ALS [196][197][198].…”

The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta‐analysis

“…In addition, 11 studies investigated CSF NfL concentration of 1239 ALS cases compared with 806 disease mimic controls, with an average concentration ratio of 3.35 (95% CI 2.19-5.12, P , 0.0001; Fig. 4B) [4,8,27,57,65,68,69,[72][73][74][75].…”

Cerebrospinal fluid neurofilament light in suspected sporadic Creutzfeldt-Jakob disease

“…The diagnostic potential of CSF NFL has been studied in the context of several neurodegenerative disorders, including Alzheimer's disease (AD) [6], Amyotrophic Lateral Sclerosis (ALS) [7][8][9], MS [10] and their related disorders, corresponding to Mild Cognitive Impairment (MCI) [6] and different Frontotemporal Dementia subtypes (FTDs) [11][12][13]. Further, a potential prognostic value in terms of disease progression and survival has been suggested for CSF NFL levels in ALS [7], and in FTD subtypes [12,14].…”