Blood neurofilament light: a critical review of its application to neurologic disease

Abstract

Neuronal injury is a universal event that occurs in disease processes that affect both the central and peripheral nervous systems. A blood biomarker linked to neuronal injury would provide a critical measure to understand and treat neurologic diseases. Neurofilament light chain (NfL), a cytoskeletal protein expressed only in neurons, has emerged as such a biomarker. With the ability to quantify neuronal damage in blood, NfL is being applied to a wide range of neurologic conditions to investigate and monitor disease including assessment of treatment efficacy. Blood NfL is not specific for one disease and its release can also be induced by physiological processes. Longitudinal studies in multiple sclerosis, traumatic brain injury, and stroke show accumulation of NfL over days followed by elevated levels over months. Therefore, it may be hard to determine with a single measurement when the peak of NfL is reached and when the levels are normalized. Nonetheless, measurement of blood NfL provides a new blood biomarker for neurologic diseases overcoming the invasiveness of CSF sampling that restricted NfL clinical application. In this review, we examine the use of blood NfL as a biologic test for neurologic disease.

Figure 1

Physiological and pathological factors increasing or decreasing the blood levels of NfL. NfL is released as a consequence of neuronal damage. A rise in NfL (red arrows) is not specific for a specific disease factor and may be caused by both neurodegenerative diseases or a head impact during sports. Cardiovascular risk factors and aging may cause subclinical damage due to silent ischemic events. NfL is not specific for the central nervous system and occurs with injury to the peripheral nervous system. BBB permeability may influence blood NfL levels (light red arrow). Some factors may contribute to a decrease in NfL (blue arrows) including an increase in blood volume associated with BMI. Pregnancy is associated with a physiological increase in NfL. Treatment that decreases neuronal damage results in lower blood NfL levels. BBB, blood–brain barrier; BMI, body‐mass‐index; CNS, central nervous system; PNS, peripheral nervous system.

Figure 2

Interpretation of NfL levels in adult and elderly patients. The relative contribution of the primary disease to the overall NfL level is affected by other causes of neuronal damage. This is particularly relevant in the older populations, where aging and comorbidities lead to a substantial variability between individuals. The increase in neuronal damage caused by the primary disease, for example, AD, may be masked by silent damage due to comorbidities. AD, Alzheimer disease; FTD, frontotemporal dementia; MS, multiple sclerosis; NfL, neurofilament light chain; TBI, traumatic brain injury.