Interpretation

Interpretation of plasma neurofilament light chain (NfL) concentrations depends on the clinical context.

Normal plasma NfL concentrations are generally consistent with the absence of neurodegeneration. In patients receiving therapy for multiple sclerosis (MS), normal or decreased NfL concentrations would suggest treatment response and a more favorable prognosis.

Increased plasma NfL concentrations are consistent with the presence of neurodegeneration. In patients with a known neurologic condition, elevated NfL or increased concentrations from an established, patient-specific baseline may indicate poorer prognosis and/or disease progression.

In multiple sclerosis, NfL is most valuable as a prognostic indicator for severity of disease, disease progression, and as an indicator of response to therapy. Baseline plasma NfL concentrations are a valuable contribution to the initial workup in patients with diagnosed or suspected MS and should be interpreted in the context of other clinical information. The Consortium of Multiple Sclerosis Centers recommends measurement of blood NfL at baseline and regular follow-up (3-6 months) for obtaining prognostic information and evaluating treatment response.(1) Elevated baseline or increasing NfL concentrations can predict multiple sclerosis relapses and other disease activity. The use of blood NfL in serial disease monitoring and treatment response has been evaluated in various prospective clinical trials. Reductions in NfL concentrations after different treatments tend to follow the hierarchy of treatment efficacy, with greatest reductions observed with the most intensive treatments. A study that included over 1000 patients with MS receiving various treatments, reported the largest reductions in plasma NfL concentrations following alemtuzumab treatment (54% reduction), and the smallest reduction with teriflunomide treatment (7%).(2)

The nonspecific increase of NfL in a number of neurodegenerative disorders reduces the utility of NfL for differentiation of Alzheimer Disease (AD) from other cause of dementia. Measuring NfL in the context of AD likely has limited clinical utility.

In amyotrophic lateral sclerosis (ALS), NfL concentrations have been suggested to be able to discriminate ALS from ALS-mimics. NfL concentrations at symptom onset may be prognostic of disease progression rate and may be used to stratify patients into groups with a similar prognosis in clinical trials. Blood NfL concentrations remain relatively stable throughout the disease. A longitudinal decline in NfL concentrations has been described with some ALS treatments. For example, the US Food and Drug Administration has approved Qalsody (tofersen) to treat patients with ALS associated with a genetic variant in the superoxide dismutase 1 (SOD1) gene. The approval was based on a reduction in plasma NfL concentrations at the end treatment compared to the placebo arm. For other ALS therapies such as riluzole, NfL concentrations have been reported not to be useful for monitoring treatment effects.

Parkinson disease (PD) patients with elevated NfL concentrations have been reported to have worse cognitive decline, brain cortical atrophy, and motor scores. Blood NfL concentrations in atypical forms of Parkinson disease are higher than in PD and may be used to help differentiate PD from atypical parkinsonian disorders such as progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy.

In frontotemporal dementia (FTD), NfL concentrations differ according to the underlying mutation - they are highest in people with the GRN mutation and lowest in people with the MAPT mutation. These levels rise in the presymptomatic stages of FTD, and the timing of preclinical increases differs with the underlying mutation.

In traumatic brain injury (TBI), blood NfL concentrations have been evaluated both in the context of mild TBI (mTBI) diagnosis (acute setting) and prognosis (outcome prediction). In the acute setting, the utility of NfL in identifying mTBI within 24 hours of an injury has been controversial, likely due to the different timepoints used in studies for evaluating NfL concentrations after the injury (ranging from 1-, 4-, 6-, 12-, and 24-hours post-injury). A recent 2022 review describes the findings of six different publications looking at the role of NfL in acute mTBI concluding that, although the clinical usefulness of blood NfL for acute diagnosis of mild TBI is uncertain, the biomarker shows promise for the prognosis of complications of mild TBI, neuroimaging findings and recovery when measured during the first days to weeks after injury.(3)

In hypoxic–ischemic brain injury, NfL is a promising prognostic marker after cardiac arrest. NfL concentrations increase within the first 24 hours after cardiac arrest and the increased concentrations persist for days to months. A recent meta-analysis showed that elevated NfL concentrations 48 hours after cardiac arrest predict poor neurological outcomes.(4) Several studies have shown that the prognostic value of blood NfL in this context is higher than that of other blood biomarkers routinely used for cardiac arrest prognosis including neuron-specific enolase, S100 and total-Tau.