On November 16 the ‘Neurofilament as a Biomarker’ meeting organised by Paul Matthews (UK DRI at Imperial) and Henrik Zetterberg (UK DRI at UCL) convened a selected international group of experts who engaged in lively discussions on the neurobiology of Neurofilaments (Nfs), their clearance pathways, and their potential use as meaningful biomarkers in neurodegenerative diseases.
Nfs are heteropolymers composed of four subunits (NfL for neurofilament light; NfM for neurofilament medium; NfH for neurofilament heavy, and alpha-internexin or peripherin), each having different structural domain and functions. A complex pattern of phosphorylation and dephosphorylation events on each subunit modulates filament assembly, turnover and organisation. The role of Nfs has traditionally been associated to the regulation of axon calibre. However, over the past decade new functions for Nfs have emerged, ranging from regulation of microtubule dynamics and dendritic spine length/density to modulation of synaptic plasticity, neurotransmission and cellular metabolism. Nf gene mutations cause severe neuroaxonal disorders characterised by disrupted subunit assembly and Nf aggregation, and the stoichiometry of Nf mRNA is disrupted in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
It is thought that pathological processes causing axonal damage result in the release of Nf proteins into the extracellular space, reaching the CSF and blood. Levels of Nf proteins may thus represent a surrogate biomarker for axonal damage, and an increasing amount of studies are pointing to the potential use of CSF Nf levels (particularly NfL) as a biomarker for several neurodegenerative conditions including stroke, traumatic brain injury, ALS, Huntington’s and Alzheimer’s disease. Importantly, recent, more sensitive approaches like single molecule arrays (Simoa) are starting to allow detection of NfL in blood, which could hugely facilitate its adoption as a biomarker.
The meeting highlighted key questions and future lines of investigation that would support the adoption of NfL as a useful biomarker for prognostic profiling, treatment response and even as a treatment target.
• We still have little knowledge about NfL metabolism and kinetics – more preclinical studies are needed in healthy and disease models to better understand the degradation pathways of NfL and definitively characterise NfL fragments detected in CSF/plasma
• The turnover pathways and potential roles for NfH and NfM also need to be clarified
• There are currently no standardised assays for NfL detection, identifying a set of reference materials would help assay calibration
• A prerequisite for therapeutic decision making is a normative database that would require prospective population studies – e.g. how do NfL levels change in CSF/plasma with age in normal individuals? What is the impact of co-morbidities?
The UK DRI will certainly play a key role in providing some of the answers.
If you missed it, you can see all the slides and videos.
Author: Dr Giovanna Lalli, UK DRI Director of Scientific Affairs