Barriers in the Nervous System: Challenges and Opportunities for Novel Biomarkers in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous system would be useful, but the physical impossibility of direct sampling and analysis of the nervous system makes them challenging to validate. A highly explored option is the identification of neuronal-specific markers that could be analyzed in peripheral biofluids. This review focuses on the description of the physical and biological barriers to the central nervous system and of the composition of biofluids in which ALS disease biomarkers are actively searched. Finally, we comment on already validated biomarkers, such as the neurofilament light chain, and show the potential of extracellular vesicles (EVs) and cell-free DNA as additional biomarkers for disease prediction.

Keywords: blood–CSF barrier; blood–brain barrier; blood–spinal cord barrier; review.

Figure 1

Representation of the main physical barriers controlling the passage of molecules and biological entities from and to the nervous system. The cell composition of the blood–brain barrier (BBB) and the blood–spinal cord barrier (BSCB) is illustrated on the left. On the right are the illustrations of the blood–CSF barrier (BSCFB) and the gut–vascular barrier (GVB). The illustration was realized with Biorender ©.

Figure 2

General representation of the biological complexity of the human biofluids (CSF, blood, urine, saliva, tears) used for biomarker discovery and monitoring. Illustration realized with Biorender©. Urine collection is generally considered the least invasive, while CSF collection is the most invasive.

Figure 3

The potential of combining a single blood sample to analyze genomic material, proteins, extracellular vesicles, and metabolites. Illustration realized with Biorender ©.