Emerging molecular biomarker targets for amyotrophic lateral sclerosis

Highlights

• Novel biomarkers are critical for ALS diagnosis and prognosis, and in trials.

• pNFH and NFL have been largely studied and constitute promising ALS biomarkers.

• Novel biomarker targets are investigated and others will be discovered in the future.

Abstract

Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects upper (UMN) and lower motor (LMN) neurons. It is associated with a short survival and there is no effective treatment, in spite of a large number of clinical trials. Strong efforts have been made to identify novel disease biomarkers to support diagnosis, provide information on prognosis, to measure disease progression in trials and increase our knowledge on disease pathogenesis.

Electromyography by testing the function of the LMN can be used as a biomarker of its dysfunction. A number of electrophysiological and neuroimaging methods have been explored to identify a reliable marker of UMN degeneration. Recently, strong evidence from independent groups, large cohorts of patients and multicenter studies indicate that neurofilaments are very promising diagnostic biomarkers, in particular cerebrospinal fluid and blood levels of phosphoneurofilament heavy chain and neurofilament light chain. Furthermore, their increased levels are associated with poor prognosis.

Additional studies have been performed aiming to identify other biomarkers, which alone or in combination with neurofilaments could increase the sensitivity and the specificity of the assays. Emerging molecular marker targets are being discovered, but more studies with standardized methods are required in larger cohorts of ALS patients.

Introduction

Amyotrophic lateral sclerosis (ALS) has an incidence of 2–3/100,000 and a prevalence of 6–7/100,000 in Europe [1], [2]. Most patients die within 2–5 years after first symptoms, due to complications related to impairment of the respiratory function [3]. However, some patients have a shorter survival, in particular patients presenting with respiratory impairment [4], and others have a very slow progression surviving for more than 30 years. Generally, first symptoms occur in the age interval of 55–65 years, but disease can start in very old subjects or in very young people [5]. About 5–10% of the cases have a positive family history for this disease; but, in most cases (90–95%) there is no other affected family member — sporadic cases. The only available drug used worldwide for this disease is the Riluzole, but its effectiveness in increasing survival is modest [6]. Non-invasive ventilation is a quite accepted intervention to increase quality of life and survival of ALS patients [7]. Gastrostomy, multidisciplinary care [7], sialorrhea treatment [8] and communication aids [9] are useful to increase quality of life of ALS patients.

Strong efforts have been made to identify novel biomarkers for ALS that could be useful to support earlier diagnosis, inform about prognosis, monitor disease progression in clinical trials and provide better understanding of disease pathogenesis. Targeted approaches based on the known mechanisms of the disease have been largely explored aiming to identify deregulated molecules. On the other hand, untargeted approaches based on the systematic analysis of biomolecules using metabolomics, genomics, proteomics, glycomics and lipidomics strategies have been used with the same purpose. The biological material used in the analyses consisted of tissues from human patients, such as biofluids – blood, cerebrospinal fluid (CSF), urine – or skin, as well as samples from necropsy (spinal cord and brain). Animal and cell models of ALS deriving from known mutations associated with the disease have also constituted a source of material for analysis.

Different aspects in the search of biomarkers for ALS have been excellently reviewed by several authors [10], [11], [12], [13], [14], [15], [16], [17]. In this paper we will focus on the literature about neurofilaments, which are the most promising biomarkers for ALS at present, and also other emerging targets from the CSF, blood and urine.