Abstract
Blood neurofilament light chain (NfL) is a marker of neuro-axonal injury showing promising associations with outcomes of interest in several neurological conditions. Although initially discovered and investigated in the cerebrospinal fluid (CSF), the recent development of ultrasensitive digital immunoassay technologies has enabled reliable detection in serum/plasma, obviating the need for invasive lumbar punctures for longitudinal assessment. The most evidence for utility relates to multiple sclerosis (MS) where it serves as an objective measure of both the inflammatory and degenerative pathologies that characterise this disease. In this review, we summarise the physiology and pathophysiology of neurofilaments before focusing on the technological advancements that have enabled reliable quantification of NfL in blood. As the test case for clinical translation, we then highlight important recent developments linking blood NfL levels to outcomes in MS and the next steps to be overcome before this test is adopted on a routine clinical basis.
Highlights
More recent discoveries show that α-Internexin in the central nervous system [2] and peripherin in the peripheral nervous system [3] can be included in neurofilament heteropolymers
Some of the differences observed may correspond to analytical methodologies, this study found that neurofilament light chain (NfL) levels were higher than neurofilament heavy chain (NfH) and NfL was a better discriminator of multiple sclerosis (MS) patients from controls
Analogous to the cardiologist’s troponin, neurofilament light chain is a structural axonal protein that can be detected in the blood at elevated levels in a variety of neurological disease states which can be followed longitudinally
Summary
Neurofilaments are neuronal-specific heteropolymers conventionally considered to consist of a triplet of light (NfL), medium (NfM) and heavy (NfH) chains according to their molecular mass [1]. More recent discoveries show that α-Internexin in the central nervous system [2] and peripherin in the peripheral nervous system [3] can be included in neurofilament heteropolymers These five proteins co-assemble into the 10 nM intermediate filaments in different combinations and concentrations depending on the type of neuron, location in the axon and stage of development [4]. The primary focus of this review is the pathophysiologic relevance of NfL concentrations as they relate to neurological diseases such as MS, the vital role of neurofilaments is underlined by various human mutations that interfere with their function and homeostasis. The pathogenic potential of anti-NfL antibodies is a topic of debate as the neurofilament light chain is intracellular and presumably not amenable to immune surveillance or targeting in the healthy state. The pathogenic potential of antibodies directed against an intracellular antigen such as NfL remains debatable, these circulating antibodies could have important and unexplored implications on neurofilament metabolism in the periphery as well as interference in NfL assays which are antibody-based immunoassays
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