Neurochemical biomarkers of amyotrophic lateral sclerosis: recent developments

To provide an overview of the recent developments in the field of neurochemical biomarkers of amyotrophic lateral sclerosis (ALS).

Neurofilaments, especially NFL, have been confirmed to be good biomarkers for ALS. NFL may be diagnostically useful but its main role is as prognostic and pharmacodynamic biomarker. Inflammatory biomarkers, especially the chitinases, might also serve as pharmacodynamic biomarkers in treatment trials targeting neuroinflammation. GFAP could reflect cognitive-behavioural impairment. CSF dipeptides are diagnostic biomarkers for ALS caused by the C9ORF72 exanucleotide repeat expansion and may be used to confirm target engagement by experimental drugs. Levels of TDP-43 (virtually the ideal biomarker for ALS) in CSF and plasma have not been demonstrated to be consistently altered in ALS. However, promising advancements have been achieved in seed amplification assays for the protein, in its quantification in plasma extracellular vesicles, and in the measurement of CSF levels of a protein reflecting splicing dysfunction of TDP-43. Finally, blood phosphorylated tau has emerged as an ALS biomarker linked to lower motor neuron (or muscle) pathology.

NFL is still the best neurochemical biomarker for ALS. However, substantial advances have been recently made, especially regarding detection of TDP-43 and blood phosphorylated tau.