Peripheral Blood Neurofilament Light Chain Levels: The Neurologist's C-reactive Protein?

Gavin Giovannoni, MBBCh, PhD


Brain. 2018;141(8):2235-2237. 

In This Article

Abstract and Introduction


Neurofilament proteins are the major scaffolding proteins of axons. Neurofilaments are heteropolymers composed of light (NfL), medium (NfM) and heavy (NfH) chain subunits (Giovannoni, 2006). Pathological processes that cause axonal damage result in the release of neurofilament proteins into the extracellular space. These then diffuse into the CSF and are transported into the peripheral blood. Levels of neurofilament proteins may thus be a good surrogate for quantifying axonal damage. Numerous studies have reported on the potential utility of CSF and peripheral blood neurofilament levels as a biomarker in several diseases characterized by axonal loss, including stroke, small vessel disease, HIV infection, head injury, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, acute spinal cord injury, neuromyelitis optica and multiple sclerosis. Until recently one had to rely on measurement of neurofilament levels in CSF, which has limited its adoption. However, the emergence of the single molecule arrays (Simoa), an ultra-sensitive enzyme-linked immunosorbent assay (ELISA) technique, for measuring peripheral blood NfL levels has led to a renaissance of NfL as a biomarker in diseases including multiple sclerosis (Disanto et al., 2016; Kuhle et al., 2017; Barro et al., 2018; Siller et al., 2018). Although neurofilaments have good face validity as a biomarker, a critical question is how soon can peripheral blood NfL levels be adopted as a surrogate endpoint in the context of multiple sclerosis clinical trials? The well-established Prentice criteria for defining the necessary attributes of a surrogate endpoint require that (i) the baseline measurement of NfL is predictive of outcome; (ii) changes in NfL over time are predictive of outcome; and (iii) changes in NfL levels in response to a therapy are also predictive of outcome (Prentice, 1989).